What is the Rate of Response to Nonoperative Treatment for Hip-Related Pain? A Systematic Review With Meta-analysis.

OBJECTIVE: We aimed to (1) determine the rate of satisfactory response to nonoperative treatment for nonarthritic hip-related pain, and (2) evaluate the specific effect of various elements of physical therapy and nonoperative treatment options aside from physical therapy. DESIGN: Systematic review with meta-analysis. LITERATURE SEARCH: We searched 7 databases and reference lists of eligible studies from their inception to February 2022. STUDY SELECTION CRITERIA: We included randomized controlled trials and prospective cohort studies that compared a nonoperative management protocol to any other treatment for patients with femoroacetabular impingement syndrome, acetabular dysplasia, acetabular labral tear, and/or nonarthritic hip pain not otherwise specified. DATA SYNTHESIS: We used random-effects meta-analyses, as appropriate. Study quality was assessed using an adapted Downs and Black checklist. Certainty of evidence was assessed using the Grading of Recommendations, Assessment, Development, and Evaluations (GRADE) approach. RESULTS: Twenty-six studies (1153 patients) were eligible for qualitative synthesis, and 16 were included in the meta-analysis. Moderate certainty evidence suggests that the overall response rate to nonoperative treatment was 54% (95% confidence interval: 32%, 76%). The overall mean improvement after physical therapy treatment was 11.3 points (7.6-14.9) on 100-point patient-reported hip symptom measures (low to moderate certainty) and 22.2 points (4.6-39.9) on 100-point pain severity measures (low certainty). No definitive specific effect was observed regarding therapy duration or approach (ie, flexibility exercise, movement pattern training, and/or mobilization) (very low to low certainty). Very low to low certainty evidence supported viscosupplementation, corticosteroid injection, and a supportive brace. CONCLUSION: Over half of patients with nonarthritic hip-related pain reported satisfactory response to nonoperative treatment. However, the essential elements of comprehensive nonoperative treatment remain unclear. J Orthop Sports Phys Ther 2023;53(5):1-21. Epub 9 March 2023. doi:10.2519/jospt.2023.11666.

Hepatic epithelioid hemangioendothelioma associated with acute disseminated encephalomyelitis by a possible paraneoplastic process.

Epithelioid hemangioendothelioma (EHE) is a low-grade, malignant vascular neoplasm that frequently involves the liver, lungs, bone, and soft tissue. Although not commonly associated with a paraneoplastic syndrome, paraneoplastic syndromes in the setting of EHE have been reported. Acute disseminated encephalomyelitis (ADEM) is an acute, autoimmune, demyelinating disorder of the central nervous system that most commonly occurs after an infection or vaccination. We present the case of a 23 year old female who developed the acute onset of fevers, tremors, right sided hemiplegia, global aphasia, and incontinence of urine and stool. MRI demonstrated findings consistent with a demyelinating disorder and brain biopsy confirmed the diagnosis of ADEM. The patient's work up revealed multiple liver lesions which were biopsy proven EHE. This case report discusses the diagnosis and treatment of two concurrent rare disease processes and the possible association of the processes via a paraneoplastic syndrome.

Exploring Chemical Space with Machine Learning.

Chemical space is a concept to organize molecular diversity by postulating that different molecules occupy different regions of a mathematical space where the position of each molecule is defined by its properties. Our aim is to develop methods to explicitly explore chemical space in the area of drug discovery. Here we review our implementations of machine learning in this project, including our use of deep neural networks to enumerate the GDB13 database from a small sample set, to generate analogs of drugs and natural products after training with fragment-size molecules, and to predict the polypharmacology of molecules after training with known bioactive compounds from ChEMBL. We also discuss visualization methods for big data as means to keep track and learn from machine learning results. Computational tools discussed in this review are freely available at http://gdb.unibe.ch and https://github.com/reymond-group.

Optimizing TRPM4 inhibitors in the MHFP6 chemical space.

We recently reported 4-chloro-2-(2-chlorophenoxy)acetamido)benzoic acid (CBA) as the first potent inhibitor of TRPM4, a cation channel implicated in cardiac diseases and prostate cancer. Herein we report a structure-activity relationship (SAR) study of CBA resulting in two new potent analogs. To design and interpret our SAR we used interactive color-coded 3D-maps representing similarities between compounds calculated with MHFP6 (MinHash fingerprint up to six bonds), a new molecular fingerprint outperforming other fingerprints in benchmarking virtual screening studies. We further illustrate the general applicability of our method by visualizing the structural diversity of active compounds from benchmarking sets in relation to decoy molecules and to drugs. MHFP6 chemical space 3D-maps might be generally helpful in designing, interpreting and communicating the results of SAR studies. The modified WebMolCS is accessible at http://gdb.unibe.ch and the code is available at https://github.com/reymond-group/webMolCS for off-line use.

Design, crystal structure and atomic force microscopy study of thioether ligated d,l-cyclic antimicrobial peptides against multidrug resistant Pseudomonas aeruginosa.

Here we report a new family of cyclic antimicrobial peptides (CAMPs) targeting MDR strains of Pseudomonas aeruginosa. These CAMPs are cyclized via a xylene double thioether bridge connecting two cysteines placed at the ends of a linear amphiphilic alternating d,l-sequence composed of lysines and tryptophans. Investigations by transmission electron microscopy (TEM), dynamic light scattering and atomic force microscopy (AFM) suggest that these peptide macrocycles interact with the membrane to form lipid-peptide aggregates. Amphiphilic conformations compatible with membrane disruption are observed in high resolution X-ray crystal structures of fucosylated derivatives in complex with lectin LecB. The potential for optimization is highlighted by N-methylation of backbone amides leading to derivatives with similar antimicrobial activity but lower hemolysis.

Chemical Space: Big Data Challenge for Molecular Diversity.

Chemical space describes all possible molecules as well as multi-dimensional conceptual spaces representing the structural diversity of these molecules. Part of this chemical space is available in public databases ranging from thousands to billions of compounds. Exploiting these databases for drug discovery represents a typical big data problem limited by computational power, data storage and data access capacity. Here we review recent developments of our laboratory, including progress in the chemical universe databases (GDB) and the fragment subset FDB-17, tools for ligand-based virtual screening by nearest neighbor searches, such as our multi-fingerprint browser for the ZINC database to select purchasable screening compounds, and their application to discover potent and selective inhibitors for calcium channel TRPV6 and Aurora A kinase, the polypharmacology browser (PPB) for predicting off-target effects, and finally interactive 3D-chemical space visualization using our online tools WebDrugCS and WebMolCS. All resources described in this paper are available for public use at www.gdb.unibe.ch.

Frontiers in Medicinal Chemistry 2017 in Bern, Switzerland.

Sharing capital ideas: The 2017 Frontiers in Medicinal Chemistry (FiMC) conference, organized jointly by the German Chemical Society, the German Pharmaceutical Society, and the Swiss Chemical Society, was held at the Department of Chemistry and Biochemistry of the University of Bern in February 2017. Herein we summarize the many conference highlights, and look forward to the next FiMC meeting, to be held in Jena (Germany) in March 2018.