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Unicompartmental changes in the knee of a young athlete remains a difficult and controversial problem in orthopaedics. Excessive premature loading of articular cartilage, most often the result of a knee injury, has been shown to result in increased degenerative changes and pain in the younger patient. Instability may also contribute to the degeneration of cartilage and must therefore be considered in the treatment of osteoarthritis in the young adult. High tibial osteotomy has been described as a treatment option for malalignment in the older, less active adult and has shown promising results in a younger, more active population. Osteotomies for instability are more controversial and should be considered in more complex injury patterns. [ABSTRACT FROM AUTHOR]

Presents an abstract of the article 'The Psychoimmunological Association of Panic Disorder and Allergic Reaction,' by S. Schmidt-Traub and K.J. Bamler published in the 1997 issue of 'Journal of Clinical Psychology'.

Needs play a key role in many fields of social sciences and humanities, ranging from normative theories of distributive justice to conceptions of the welfare state. Over time, different conceptions of what counts as a need (i. e., what is considered a normatively relevant need) have been proposed. Many of them include (in one way or the other) needs for survival, decency, belonging, and autonomy. Little work has been done on how these kinds of needs are evaluated in terms of their significance for distributive justice. To begin closing this gap, we investigate the role of the four aforementioned kinds of needs for impartial observers. We do so in two empirical studies. The first study asks participants to evaluate the importance of each of the four kinds of needs separately. We find that different levels of importance are attributed to the kinds of needs, which places them in a hierarchy. The second study asks participants to make distributive decisions. Results further support the hierarchy found in the first study and, additionally, reveal that participants tend to make coherent allocation decisions., Competing Interests: The authors have declared that no competing interests exist., (Copyright: © 2023 Bauer et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.)

Defective insulin processing is associated with obesity and diabetes. Prohormone convertase 1/3 (PC1/3) is an endopeptidase required for the processing of neurotransmitters and hormones. PC1/3 deficiency and genome-wide association studies relate PC1/3 with early onset obesity. Here, we find that deletion of PC1/3 in obesity-related neuronal cells expressing proopiomelanocortin mildly and transiently change body weight and fail to produce a phenotype when targeted to Agouti-related peptide- or nestin-expressing tissues. In contrast, pancreatic β cell-specific PC1/3 ablation induces hyperphagia with consecutive obesity despite uncontrolled diabetes with glucosuria. Obesity develops not due to impaired pro-islet amyloid polypeptide processing but due to impaired insulin maturation. Proinsulin crosses the blood-brain-barrier but does not induce central satiety. Accordingly, insulin therapy prevents hyperphagia. Further, islet PC1/3 expression levels negatively correlate with body mass index in humans. In this work, we show that impaired PC1/3-mediated proinsulin processing, as observed in human prediabetes, promotes hyperphagic obesity., (© 2022. The Author(s).)

Introduction: The clinical diversity of patients presenting to the emergency department (ED) allows emergency medicine (EM) and non-EM residents to sharpen their clinical skills. In most EDs, residents self-assign patients at their discretion. Our institution transitioned from a self-assignment-system to an automated-system, after which we sought to determine the productivity of our non-EM residents compared to the previous system., Methods: In this retrospective cross-sectional study, resident productivity was measured as number of patient visits per hour and per 8.5-hour shift before and after the implementation of an automated patient assignment system in emergency department. The automated-system assigns one patient at the start of the shift, another 30 minutes later, and one patient every hour thereafter, throughout the shift., Results: 28 residents performed 406 total shifts prior to implementation and 14 residents performed 252 total shifts post-implementation. The average number of patient visits per hour significantly increased from 0.52 ± 0.18 (95% CI 0.45-0.59, IQR 0.43-0.60) to 0.82 ± 0.11 (95% CI 0.75-0.88, IQR 0.74-0.89) after implementation of our assignment system (p<0.00001; figure 1). Additionally, the average number of patient visits per 8.5-hour shift significantly increased from 4.46 ± 1.53 (CI 3.86-5.05, IQR 3.66-5.08) to 6.52 ± 0.86 (CI 6.02-7.02, IQR 5.90-7.09) after the implementation of our system (p<0.00001; figure 1)., Conclusion: These findings warrant further evaluation of the impact of patient assignment systems on trainee education., Competing Interests: The authors have no conflicts of interest to report.

In virtually any practical field or application, discovering and implementing near-optimal decision strategies is essential for achieving desired outcomes. Workflow planning is one of the most common and important problems of this kind, as sub-optimal decision-making may create bottlenecks and delays that decrease efficiency and increase costs. Recently, machine learning has been used to attack this problem, but unfortunately, most proposed solutions are "black box" algorithms with underlying logic unclear to humans. This makes them hard to implement and impossible to trust, significantly limiting their practical use. In this work, we propose an alternative approach: using machine learning to generate optimal, comprehensible strategies which can be understood and used by humans directly. Through three common decision-making problems found in scheduling, we demonstrate the implementation and feasibility of this approach, as well as its great potential to attain near-optimal results., Competing Interests: The authors have declared that no competing interests exist.

In order to circumvent the limited access and donor variability of human primary alveolar cells, directed differentiation of human pluripotent stem cells (hiPSCs) into alveolar-like cells, provides a promising tool for respiratory disease modeling and drug discovery assays. In this work, a unique, miniaturized 96-Transwell microplate system is described where hiPSC-derived alveolar-like cells were cultured at an air-liquid interface (ALI). To this end, hiPSCs were differentiated into lung epithelial progenitor cells (LPCs) and subsequently matured into a functional alveolar type 2 (AT2)-like epithelium with monolayer-like morphology. AT2-like cells cultured at the physiological ALI conditions displayed characteristics of AT2 cells with classical alveolar surfactant protein expressions and lamellar-body like structures. The integrity of the epithelial barriers between the AT2-like cells was confirmed by applying a custom-made device for 96-parallelized transepithelial electric resistance (TEER) measurements. In order to generate an IPF disease-like phenotype in vitro, the functional AT2-like cells were stimulated with cytokines and growth factors present in the alveolar tissue of IPF patients. The cytokines stimulated the secretion of pro-fibrotic biomarker proteins both on the mRNA (messenger ribonucleic acid) and protein level. Thus, the hiPSC-derived and cellular model system enables the recapitulation of certain IPF hallmarks, while paving the route towards a miniaturized medium throughput approach of pharmaceutical drug discovery., (© 2021. The Author(s).)

The reprogramming of a patient's immune system through genetic modification of the T cell compartment with chimeric antigen receptors (CARs) has led to durable remissions in chemotherapy-refractory B cell cancers. Targeting of solid cancers by CAR-T cells is dependent on their infiltration and expansion within the tumor microenvironment, and thus far, fewer clinical responses have been reported. Here, we report a phase 1 study (NCT02761915) in which we treated 12 children with relapsed/refractory neuroblastoma with escalating doses of second-generation GD2-directed CAR-T cells and increasing intensity of preparative lymphodepletion. Overall, no patients had objective clinical response at the evaluation point +28 days after CAR-T cell infusion using standard radiological response criteria. However, of the six patients receiving ≥10 8 /meter 2 CAR-T cells after fludarabine/cyclophosphamide conditioning, two experienced grade 2 to 3 cytokine release syndrome, and three demonstrated regression of soft tissue and bone marrow disease. This clinical activity was achieved without on-target off-tumor toxicity. Targeting neuroblastoma with GD2 CAR-T cells appears to be a valid and safe strategy but requires further modification to promote CAR-T cell longevity., (Copyright © 2020 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.)

Purpose: AT13148 is an oral AGC kinase inhibitor, which potently inhibits ROCK and AKT kinases. In preclinical models, AT13148 has been shown to have antimetastatic and antiproliferative activity., Patients and Methods: The trial followed a rolling six design during dose escalation. An intrapatient dose escalation arm to evaluate tolerability and a biopsy cohort to study pharmacodynamic effects were later added. AT13148 was administered orally three days a week (Mon-Wed-Fri) in 28-day cycles. Pharmacokinetic profiles were assessed using mass spectrometry and pharmacodynamic studies included quantifying p-GSK3β levels in platelet-rich plasma (PRP) and p-cofilin and p-MLC2 levels in tumor biopsies., Results: Fifty-one patients were treated on study. The safety of 5-300 mg of AT13148 was studied. Further, the doses of 120-180-240 mg were studied in an intrapatient dose escalation cohort. The dose-limiting toxicities included hypotension (300 mg), pneumonitis, and elevated liver enzymes (240 mg), and skin rash (180 mg). The most common side effects were fatigue, nausea, headaches, and hypotension. On the basis of tolerability, 180 mg was considered the maximally tolerated dose. At 180 mg, mean C max and AUC were 400 nmol/L and 13,000 nmol/L/hour, respectively. At 180 mg, ≥50% reduction of p-cofilin was observed in 3 of 8 posttreatment biopsies., Conclusions: AT13148 was the first dual potent ROCK-AKT inhibitor to be investigated for the treatment of solid tumors. The narrow therapeutic index and the pharmacokinetic profile led to recommend not developing this compound further. There are significant lessons learned in designing and testing agents that simultaneously inhibit multiple kinases including AGC kinases in cancer., (©2020 American Association for Cancer Research.)

Background: Macrophages (Mф) can be M1/M2 polarized by Th1/2 signals, respectively. M2-like Mф are thought to be important in asthma pathogenesis, and M1-like in anti-infective immunity, however their roles in virus-induced asthma exacerbations are unknown. Our objectives were (i) to assess polarised Mф phenotype responses to rhinovirus (RV) infection in vitro and (ii) to assess Mф phenotypes in healthy subjects and people with asthma before and during experimental RV infection in vivo., Methods: We investigated characteristics of polarized/unpolarized human monocyte-derived Mф (MDM, from 3-6 independent donors) in vitro and evaluated frequencies of M1/M2-like bronchoalveolar lavage (BAL) Mф in experimental RV-induced asthma exacerbation in 7 healthy controls and 17 (at baseline) and 18 (at day 4 post infection) people with asthma., Findings: We observed in vitro: M1-like but not M2-like or unpolarized MDM are potent producers of type I and III interferons in response to RV infection (P<0.0001), and M1-like are more resistant to RV infection (P<0.05); compared to M1-like, M2-like MDM constitutively produced higher levels of CCL22/MDC (P = 0.007) and CCL17/TARC (P<0.0001); RV-infected M1-like MDM were characterized as CD14 + CD80 + CD197 + (P = 0.002 vs M2-like, P<0.0001 vs unpolarized MDM). In vivo we found reduced percentages of M1-like CD14 + CD80 + CD197 + BAL Mф in asthma during experimental RV16 infection compared to baseline (P = 0.024)., Interpretation: Human M1-like BAL Mф are likely important contributors to anti-viral immunity and their numbers are reduced in patients with allergic asthma during RV-induced asthma exacerbations. This mechanism may be one explanation why RV-triggered clinical and pathologic outcomes are more severe in allergic patients than in healthy subjects., Funding: ERC FP7 Advanced grant 233015, MRC Centre Grant G1000758, Asthma UK grant 08-048, NIHR Biomedical Research Centre funding scheme, NIHR BRC Centre grant P26095, the Predicta FP7 Collaborative Project grant 260895, RSF grant 19-15-00272, Megagrant No 14.W03.31.0024., Competing Interests: Declaration of Competing Interest Dr. Johnston reports personal fees from Therapeutic Frontiers, personal fees from Virtus Respiratory Research, personal fees from Myelo Therapeutics GmbH, personal fees from Concert Pharmaceuticals, personal fees from Bayer, personal fees from Synairgen, personal fees from Novartis, personal fees from Boehringer Ingelheim, personal fees from Chiesi, personal fees from Gerson Lehrman Group, personal fees from resTORbio, personal fees from Bioforce, personal fees from Materia Medical Holdings, personal fees from PrepBio Pharma, personal fees from Pulmotect, personal fees from Virion Health, personal fees from Lallemand Pharma, personal fees from AstraZeneca, outside the submitted work; In addition, Dr. Johnston has a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Anti-virus therapy for respiratory diseases. UK patent application No. GB 0405634.7, 12 March 2004. with royalties paid, a patent Wark PA, Johnston SL, Holgate ST, Davies DE. Interferon-Beta for Anti-Virus Therapy for Respiratory Diseases. International Patent Application No. PCT/B05/50031, 12 March 2004. with royalties paid, and a patent Davies DE, Wark PA, Holgate ST, Johnston SL. Interferon Lambda therapy for the treatment of respiratory disease. UK patent application No. 6779645.9, granted 15th August 2012. licensed. Rudolf Valenta has received research grants from the Austrian Science Fund (FWF) and Viravaxx, Vienna, Austria and serves as a consultant for Viravaxx. The other authors do not have any conflict of interest., (Copyright © 2020 The Authors. Published by Elsevier B.V. All rights reserved.)

Gestational diabetes mellitus (GDM) is one of the most common diseases associated with pregnancy, however, the underlying mechanisms remain unclear. Based on the well documented role of inflammation in type 2 diabetes, the aim was to investigate the role of inflammation in GDM. We established a mouse model for GDM on the basis of its two major risk factors, obesity and aging. In these GDM mice, we observed increased Interleukin-1β (IL-1β) expression in the uterus and the placenta along with elevated circulating IL-1β concentrations compared to normoglycemic pregnant mice. Treatment with an anti-IL-1β antibody improved glucose-tolerance of GDM mice without apparent deleterious effects for the fetus. Finally, IL-1β antagonism showed a tendency for reduced plasma corticosterone concentrations, possibly explaining the metabolic improvement. We conclude that IL-1β is a causal driver of impaired glucose tolerance in GDM.

Objectives: To (i) investigate alterations in homotopic functional connectivity (hfc) in concussed patients relative to healthy controls (HC) and to (ii) interrogate whether hfc in concussed patients normalized during the recovery process. The relationship between symptom recovery and change in hfc was assessed using post-hoc analyses., Methods: This study included 15 concussed patients (mean age = 39.1, SD = 10.1; sex: 13 females, 2 males) and 15 HC (mean age = 39.1, SD = 11.7; sex: 13 females, 2 males). Hfc patterns were interrogated using resting-state magnetic resonance imaging (rs-MRI) for 29 a priori selected pain-processing regions. Concussed patients underwent imaging at two time-points; at 1-month post-concussion (mean time following concussion: 28 days, SD = 9.5) and again at 5-months post-concussion (mean time following concussion: 121 days, SD = 13). At both time-points, symptoms associated with concussion were assessed using the Sports Concussion Assessment Tool (SCAT-3)., Results: Concussed patients had significantly weaker hfc in the following six regions 1-month post-concussion compared to HC: middle cingulate, posterior insula, middle occipital, spinal trigeminal nucleus, precentral and the pulvinar. There were no regions of significantly stronger hfc in concussed patients relative to HC. Longitudinally, patients showed significant symptom recovery 5-months post-concussion and had significant strengthening of hfc patterns in seven homotopic ROIs: middle cingulate, posterior insula, middle occipital, secondary somatosensory area, spinal trigeminal nucleus, precentral, and the pulvinar. Post-hoc analyses indicated a significant negative correlation between somatosensory functional connectivity strengthening and symptom severity., Conclusion: At 1-month post-concussion, patients had significantly weaker hfc in a number of pain-processing regions relative to HC. However, over a period of 5-months, region-pair connectivity showed significant recovery and normalization. Those patients with more successful symptom recovery at 5-months post-concussion had more functional somatosensory strengthening, suggesting an association between functional strengthening and post-concussion symptom recovery., Competing Interests: The authors have declared that no competing interests exist.

Background: Enhancers are genomic regulatory elements conferring spatiotemporal and signal-dependent control of gene expression. Recent evidence suggests that enhancers can generate noncoding enhancer RNAs, but their (patho)biological functions remain largely elusive., Methods: We performed chromatin immunoprecipitation-coupled sequencing of histone marks combined with RNA sequencing of left ventricular biopsies from experimental and genetic mouse models of human cardiac hypertrophy to identify transcripts revealing enhancer localization, conservation with the human genome, and hypoxia-inducible factor 1α dependence. The most promising candidate, hypoxia-inducible enhancer RNA ( HERNA)1, was further examined by investigating its capacity to modulate neighboring coding gene expression by binding to their gene promoters by using chromatin isolation by RNA purification and λN-BoxB tethering-based reporter assays. The role of HERNA1 and its neighboring genes for pathological stress-induced growth and contractile dysfunction, and the therapeutic potential of HERNA1 inhibition was studied in gapmer-mediated loss-of-function studies in vitro using human induced pluripotent stem cell-derived cardiomyocytes and various in vivo models of human pathological cardiac hypertrophy., Results: HERNA1 is robustly induced on pathological stress. Production of HERNA1 is initiated by direct hypoxia-inducible factor 1α binding to a hypoxia-response element in the histoneH3-lysine27acetylation marks-enriched promoter of the enhancer and confers hypoxia responsiveness to nearby genes including synaptotagmin XVII, a member of the family of membrane-trafficking and Ca 2+ -sensing proteins and SMG1, encoding a phosphatidylinositol 3-kinase-related kinase. Consequently, a substrate of SMG1, ATP-dependent RNA helicase upframeshift 1, is hyperphoshorylated in a HERNA1- and SMG1-dependent manner. In vitro and in vivo inactivation of SMG1 and SYT17 revealed overlapping and distinct roles in modulating cardiac hypertrophy. Finally, in vivo administration of antisense oligonucleotides targeting HERNA1 protected mice from stress-induced pathological hypertrophy. The inhibition of HERNA1 postdisease development reversed left ventricular growth and dysfunction, resulting in increased overall survival., Conclusions: HERNA1 is a novel heart-specific noncoding RNA with key regulatory functions in modulating the growth, metabolic, and contractile gene program in disease, and reveals a molecular target amenable to therapeutic exploitation.

The pursuit of increased efficiency and quality of clinical care based on the analysis of workflow has seen the introduction of several modern technologies into medical environments. Electronic health records (EHRs) remain central to analysis of workflow, owing to their wide-ranging impact on clinical processes. The two most common interventions to facilitate EHR-related workflow analysis are automated location tracking using sensor-based technologies and EHR usage data logs. However, to maximize the potential of these technologies, and especially to facilitate workflow redesign, it is necessary to overlay these quantitative findings on the contextual data from qualitative methods such as ethnography. Such a complementary approach promises to yield more precise measures of clinical workflow that provide insights into how redesign could address inefficiencies. In this paper, we categorize clinical workflow in the Emergency Department (ED) into three types (perceived, real and ideal) to create a structured approach to workflow redesign using the available data. We use diverse data sources: sensor-based location tracking through Radio-Frequency Identification (RFID), summary EHR usage data logs, and data from physician interviews augmented by direct observations (through clinician shadowing). Our goal is to discover inefficiencies and bottlenecks that can be addressed to achieve a more ideal workflow state relative to its real and perceived state. We thereby seek to demonstrate a novel data-driven approach toward iterative workflow redesign that generalizes for use in a variety of settings. We also propose types of targeted support or adjustments to offset some of the inefficiencies we noted., (Copyright © 2019. Published by Elsevier Inc.)

In drug discovery, there is an increasing demand for more physiological in vitro models that recapitulate the disease situation in patients. Human induced pluripotent stem (hiPS) cell-derived model cells could serve this purpose. To date, several directed differentiation approaches have been described to generate definitive endoderm (DE) from hiPS cells, but protocols suitable for drug development and high-throughput screening (HTS) have not been reported yet. In this work, a large-scale expansion of hiPS cells for high-throughput adaption is presented and an optimized stepwise differentiation of hiPS cells into DE cells is described. The produced DE cells were demonstrated to express classical DE markers on the gene expression and protein level. The here described DE cells are multipotent progenitors and act as starting points for a broad spectrum of endodermal model cells in HTS and other areas of drug discovery.

Human induced pluripotent stem (hiPS) cell-derived neurons promise to provide better model cells for drug discovery in the context of neurodegenerative and neuropsychiatric diseases. The neuronal differentiation protocol described encompasses a cellular amplification phase for hiPS-derived neural progenitor (NP) cells. Thus, the combination of growth factor-driven expansion and inhibition of notch (GRINCH) enabled the scalable production of neurons in sufficient numbers to meet the immense material needs of a high-throughput screening (HTS) campaign. These GRINCH cells matured in 384-well microplates display neuronal markers and electrophysiological activity. The differentiation protocol was applicable to various human hiPS cell clones. In a finding and profiling campaign for modulators of the tropomyosin receptor kinase B (TrkB), the GRINCH neurons were shown to be suitable for measuring the phosphorylation and downstream signaling of the endogenously expressed TrkB. The employed techniques in the amplified luminescent proximity homogeneous assay (Alpha) and the high-throughput reverse transcription polymerase chain reaction (RT-PCR) format are transferable to other pharmaceutical drug targets. Together with the GRINCH neurons, these detection technologies open new experimental routes with tremendous potential for early drug discovery.