Prosthetic arthroplasty of the proximal interphalangeal joint using a surface replacing implant (CapFlex-PIP): 3-year outcomes.

Level of evidence: IV.

Personalized embryo transfer reduces success rates because endometrial receptivity analysis fails to accurately identify the window of implantation.

After more than a decade of increasingly widespread clinical use, personalized embryo transfer guided by endometrial receptivity analysis (ERA) remains controversial and unproven. One key element missing from the historical literature is the recognition that potential benefits from personalized embryo transfer are entirely dependent on the accuracy and predictive value of the ERA test. Results from the first comprehensive clinical trial, designed in a way that allowed independent evaluation of both potential benefits of personalized embryo transfer and the predictive value of the ERA test upon which it is based, were recently published. However, the authors failed to conduct an appropriate analysis or recognize the significance of their results. Here, we present a simple reanalysis of data from this otherwise excellent randomized controlled trial, demonstrating for the first time that the ERA was unable to identify the window of implantation as purported and that, as a result, personalized embryo transfer based on the ERA actually reduced rather than increased the birth rates. Based on these results and the lack of any contradictory evidence, it is our opinion that all clinical use of ERA-guided personalized embryo transfer should be discontinued immediately, outside of a controlled experimental setting with appropriate informed consent of all participating patients.

The stiff proximal interphalangeal joint - an unsolved problem?

The proximal interphalangeal joint is critical for good hand function. Its anatomical complexities often predispose it to stiffness, involving damage to one or more structures. Improving or resolving the stiffness and increasing the range of motion require an accurate assessment and understanding of the pathogenesis. The surgical strategy can then be tailored accordingly. In some cases, restoration to pre-injury level may not be possible and this condition still represents an unsolved problem in hand surgery.Level of evidence: V.

[Indications for and Limits of conservative Treatment in Hand Infections]. / Indikationen und Grenzen der konservativen Therapie bei Infektionen an der Hand.

The treatment of infections of the hand is an important part in hand surgery. Despite oft new antibiotic therapy there is a major part of surgical intervention. But there are certain cases in which a conservative treatment is indicated if a closed control is provided. Important is a careful examination, a detailed anamnesis of profession, hobby, animal or human contact, journey and secondary disease. Apart from antibiotics, limited immobilisation, physical conservation, moist dressing and pain management are important factors. In case of a conservative therapy, attention must be payed to the kind of infection and secondary diseases because there is a higher risk for complications, combined Infections and atypical pathogens in immunosuppressed patients. Typical indications for conservative treatment are erysipelas, cellulitis, early stages of felon and paronychia. Rare indications are infections with Erysipelothrix rhusiopathiae, Herpes simplex and fungal pathogens. No indications are symptoms longer than 2 days, abscess, bacterial infections of tendons, necrotizing fasciitis and empyema.

[Resection arthoplasty of the trapezium with ligament reconstruction and tendon interposition and variations]. / Resektionsarthroplastik des Daumensattelgelenks mit ihren Varianten.

OBJECTIVE: Creation of a pain-free, flexible and stable (pseudo) joint between the carpus and the base of the 1st metacarpal bone. INDICATIONS: Painful carpometacarpal (CMC)­I joint due to primary or secondary osteoarthritis, CMC­I instability. CONTRAINDICATIONS: Carpal instability, local infection, tumors. SURGICAL TECHNIQUE: Resection of the trapezium (and of the arthritic joint surfaces in CMC­I and STT [scaphoid-trapezium-trapezoid-joint]), stabilization of the base of the 1st metacarpal bone by suspension with a distally pedicled strip of the flexor carpi radialis tendon or variants thereof. POSTOPERATIVE MANAGEMENT: Immobilization in a splint for 3-5 weeks, followed by hand therapy. RESULTS: Worldwide for almost 40 years, regardless of the exact technique, almost always (90%) significant pain reduction, increased strength in the grip and slightly less in the pinch grip, very good mobility, 85-95% very satisfied patients and very good long-term results.

[Revision of failed resection arthroplasty of the CMC-1 joint using a costochondral graft]. / Revision der fehlgeschlagenen Resektionsarthroplastik des Daumensattelgelenkes unter Verwendung eines Knochen-Knorpel-Transplantats von der Rippe.

OBJECTIVE: To correct and prevent the proximalisation of the 1st ray by safe stabilisation using an autologous costochondral graft. Reduction of pain and maintaining good pinch and grip strength while preserving the important opposition of the thumb. INDICATIONS: Painful proximalisation of the 1st ray after failed trapeziectomy with contact between the base of the 1st metacarpal and the trapezoid or scaphoid. CONTRAINDICATIONS: Painful conditions following trapeziectomy for other causes. SURGICAL TECHNIQUE: Perioperative antibiotic prophylaxis is required. Extension of the previous incision and exposure of the sensitive radial branches and the radial artery. Longitudinal incision of the capsule and excision of the scar from the trapezium cavity. Dissection of the scar tissue directly around the metacarpal 1 base. After longitudinal resection of the oblique trapezoid surface, insertion of a suture anchor into the scaphoid joint surface close to the trapezoid. Removal of an approximately 2 cm long piece of rib cartilage from the middle costal arch. Insertion of the costochondral graft into the trapezium space and fixation with the suture anchor. Stable capsule closure. Suction drain. Skin suture. Thumb-forearm splint. POSTOPERATIVE MANAGEMENT: Postoperative immobilisation of the carpometacarpal (CMC)-1 joint for 4 weeks in medium abduction position. In case of uneventful wound healing also with a well-fitting orthosis. Afterwards independent movement exercises and exercises in warm water. Hand therapy only in case of difficult mobilisation at the earliest 2 months after surgery. RESULTS: From 2015-2018, 18 patients underwent surgery using this technique. The follow-up was at least 2 years after surgery. Of the 15 patients available for follow-up, 93% were classified as good and improved according to the Conolly-Rath score.

Assessment of Low-Grade Meniscal and Cartilage Damage of the Knee at 7 T: A Comparison to 3 T Imaging With Arthroscopic Correlation.

OBJECTIVES: The aim of this study was to compare the assessment of low-grade meniscal tears and cartilage damage in ultrahigh-field magnetic resonance imaging (MRI) at 7 T to routine clinical MRI at 3 T. MATERIALS AND METHODS: This study was approved by the local ethics committee, and written informed consent was obtained from each patient. Forty-one patients with suspected meniscal damage or mild osteoarthritis (Kellgren-Lawrence score, 0-2) received 7 T as well as routine clinical 3 T consecutively. The imaging protocol at both field strengths consisted of PD-weighted imaging with more than doubled resolution at 7 T. Images were read blinded regarding field strength and patient characteristics by 3 readers with different experience in musculoskeletal MRI (3 years, 6 years, and 10 years) according to a modified whole-organ MRI score of the knee in osteoarthritis and the Score of the International Cartilage Repair Society. Arthroscopic reports as a criterion standard were available for 12 patients. A multifactorial mixed model analysis was performed. RESULTS: The mean cumulated diagnostic score at 7 T was significantly closer to the criterion standard compared with 3 T in patients where criterion standard was available (P < 0.001). In all 41 patients, the damages were rated more severely at 7 T reflected by a mean higher cumulative score in cartilage (P < 0.001) and in the meniscus (P < 0.001). No difference in interreader variability between 3 T and 7 T was observed. Imaging acquisition time was nearly identical. CONCLUSIONS: Morphologic imaging of cartilage and meniscal damage of the knee in ultrahigh-field MRI at 7 T with PD-weighted TSE sequences seemed to have a significantly higher diagnostic accuracy than 3 T and can be performed with equal acquisition times while exploiting higher resolution of 7 T.

Glucose Fluctuations are Not Modulated by the Proportion of Calories from Macronutrients or Spontaneous Total Energy Expenditure in Adults with Cystic Fibrosis.

OBJECTIVES: To determine the modifiable factors affecting glucose variability in people with cystic fibrosis (CF). CF-related diabetes (CFRD) is the most common complication of CF, and its presence increases morbidity and mortality in patients. Patients with CF (with and without CFRD) have potentially harmful glucose fluctuations and glucose excursions when compared to healthy adults. Carbohydrate intake and exercise have been shown to affect glycemia. Therefore, our hypothesis was that the proportion of energy from carbohydrates and total energy expenditure (TEE) would influence glucose fluctuations in adults with CF. METHODS: A cross-sectional study involved 36 patients with CF, in whom continuous glucose monitoring systems were installed. Glucose fluctuations were then quantified using 3 indexes: mean amplitude of glucose excursions, standard deviation and coefficient of variation. Patients filled out a 3-day food diary to quantify energy intake and the proportions of calories from carbohydrates, fats and proteins, and they wore Sensewear Armbands to estimate spontaneous TEE and footsteps walked. Glucose tolerance status was determined using oral glucose tolerance tests. RESULTS: Patients with CF with normal and impaired glucose tolerance had fewer glucose fluctuations than patients with CFRD (p<0.05). However, linear regression models used to determine whether nutrition or energy expenditure affects glucose fluctuations demonstrated that energy, the proportion of carbohydrates, of fat and of protein, TEE or the number of footsteps walked did not affect glucose fluctuation indexes (p>0.05). CONCLUSIONS: TEE and the proportion of energy from carbohydrates did not affect glucose fluctuations in adults with CF.

Biomarker candidates for the detection of an infectious etiology of febrile neutropenia.

PURPOSE: Infections and subsequent septicemia are major complications in neutropenic patients with hematological malignancies. Here, we identify biomarker candidates for the early detection of an infectious origin, and monitoring of febrile neutropenia (FN). METHODS: Proteome, metabolome, and conventional biomarkers from 20 patients with febrile neutropenia without proven infection (FNPI) were compared to 28 patients with proven infection, including 17 patients with bacteremia. RESULTS: Three peptides (mass to charge ratio 1017.4-1057.3; p-values 0.011-0.024), six proteins (mass to charge ratio 6881-17,215; p-values 0.002-0.004), and six phosphatidylcholines (p-values 0.007-0.037) were identified that differed in FNPI patients compared to patients with infection or bacteremia. Seven of these marker candidates discriminated FNPI from infection at fever onset with higher sensitivity and specificity (ROC-AUC 0.688-0.824) than conventional biomarkers i.e., procalcitonin, C-reactive protein, or interleukin-6 (ROC-AUC 0.535-0.672). In a post hoc analysis, monitoring the time course of four lysophosphatidylcholines, threonine, and tryptophan allowed for discrimination of patients with or without resolution of FN (ROC-AUC 0.648-0.919) with higher accuracy compared to conventional markers (ROC-AUC 0.514-0.871). CONCLUSIONS: Twenty-one promising biomarker candidates for the early detection of an infectious origin or for monitoring the course of FN were found which might overcome known shortcomings of conventional markers.

The Flavonoid Isoliquiritigenin Reduces Lung Inflammation and Mouse Morbidity during Influenza Virus Infection.

The host response to influenza virus infection is characterized by an acute lung inflammatory response in which intense inflammatory cell recruitment, hypercytokinemia, and a high level of oxidative stress are present. The sum of these events contributes to the virus-induced lung damage that leads to high a level of morbidity and mortality in susceptible infected patients. In this context, we identified compounds that can simultaneously reduce the excessive inflammatory response and the viral replication as a strategy to treat influenza virus infection. We investigated the anti-inflammatory and antiviral potential activities of isoliquiritigenin (ILG). Interestingly, we demonstrated that ILG is a potent inhibitor of influenza virus replication in human bronchial epithelial cells (50% effective concentration [EC50] = 24.7 µM). In addition, our results showed that this molecule inhibits the expression of inflammatory cytokines induced after the infection of cells with influenza virus. We demonstrated that the anti-inflammatory activity of ILG in the context of influenza virus infection is dependent on the activation of the peroxisome proliferator-activated receptor gamma pathway. Interestingly, ILG phosphate (ILG-p)-treated mice displayed decreased lung inflammation as depicted by reduced cytokine gene expression and inflammatory cell recruitment. We also demonstrated that influenza virus-specific CD8(+) effector T cell recruitment was reduced up to 60% in the lungs of mice treated with ILG-p (10 mg/kg) compared to that in saline-treated mice. Finally, we showed that administration of ILG-p reduced lung viral titers and morbidity of mice infected with the PR8/H1N1 virus.

Prospective heterotopic ossification progenitors in adult human skeletal muscle.

Skeletal muscle has strong regenerative capabilities. However, failed regeneration can lead to complications where aberrant tissue forms as is the case with heterotopic ossification (HO), in which chondrocytes, osteoblasts and white and brown adipocytes can arise following severe trauma. In humans, the various HO cell types likely originate from multipotent mesenchymal stromal cells (MSCs) in skeletal muscle, which have not been identified in humans until now. In the present study, adherent cells from freshly digested skeletal muscle tissue were expanded in defined culture medium and were FACS-enriched for the CD73(+)CD105(+)CD90(-) population, which displayed robust multilineage potential. Clonal differentiation assays confirmed that all three lineages originated from a single multipotent progenitor. In addition to differentiating into typical HO lineages, human muscle resident MSCs (hmrMSCs) also differentiated into brown adipocytes expressing uncoupling protein 1 (UCP1). Characterizing this novel multipotent hmrMSC population with a brown adipocyte differentiation capacity has enhanced our understanding of the contribution of non-myogenic progenitor cells to regeneration and aberrant tissue formation in human skeletal muscle.

Matriptase proteolytically activates influenza virus and promotes multicycle replication in the human airway epithelium.

Influenza viruses do not encode any proteases and must rely on host proteases for the proteolytic activation of their surface hemagglutinin proteins in order to fuse with the infected host cells. Recent progress in the understanding of human proteases responsible for influenza virus hemagglutinin activation has led to the identification of members of the type II transmembrane serine proteases TMPRSS2 and TMPRSS4 and human airway trypsin-like protease; however, none has proved to be the sole enzyme responsible for hemagglutinin cleavage. In this study, we identify and characterize matriptase as an influenza virus-activating protease capable of supporting multicycle viral replication in the human respiratory epithelium. Using confocal microscopy, we found matriptase to colocalize with hemagglutinin at the apical surface of human epithelial cells and within endosomes, and we showed that the soluble form of the protease was able to specifically cleave hemagglutinins from H1 virus, but not from H2 and H3 viruses, in a broad pH range. We showed that small interfering RNA (siRNA) knockdown of matriptase in human bronchial epithelial cells significantly blocked influenza virus replication in these cells. Lastly, we provide a selective, slow, tight-binding inhibitor of matriptase that significantly reduces viral replication (by 1.5 log) of H1N1 influenza virus, including the 2009 pandemic virus. Our study establishes a three-pronged model for the action of matriptase: activation of incoming viruses in the extracellular space in its shed form, upon viral attachment or exit in its membrane-bound and/or shed forms at the apical surface of epithelial cells, and within endosomes by its membrane-bound form where viral fusion takes place.

Multivalent design of apoptosis-inducing bid-BH3 peptide-oligosaccharides boosts the intracellular activity at identical overall peptide concentrations.

Multivalent peptide-oligosaccharide conjugates were prepared and used to investigate the multivalency effect concerning the activity of Bid-BH3 peptides in live cells. Dextran oligosaccharides were carboxyethylated selectively in the 2-position of the carbohydrate units and activated for the ligation of N-terminally cysteinylated peptides. Ligation through maleimide coupling was found to be superior to the native chemical ligation protocol. Monomeric Bid-BH3 peptides were virtually inactive, whereas pentameric peptide conjugates induced apoptosis up to 20-fold stronger at identical peptide concentrations. Comparison of lowly multivalent and highly multivalent peptide dextrans proved a multivalency effect in life cells which was specific for the BH3 peptide sequence.

Plasma biomarkers and cystic fibrosis lung disease.

PURPOSE: The purpose of this study was to determine whether plasma biomarkers reflect changes in lung function and respiratory exacerbations associated with CF lung disease. METHODS: Plasma human leukocyte elastase/alpha1 antitrypsin complex (pHLE complex) values were measured in 28 adult CF patients and 47 healthy volunteers and correlated with forced expiratory volume (FEV1) and forced vital capacity (FVC). pHLE complexes were studied during respiratory exacerbations and after antibiotic therapy. Plasma cytokines and sialic acid were also measured. RESULTS: pHLE complexes were increased in CF patients (p < 0.01), were inversely correlated with FEV1 (r = 0.71) and FVC (r = 0.67) and returned to normal levels after intravenous antibiotics (p < 0.001). Plasma cytokines did not correlate with lung function. Total sialic acid increased during CF respiratory exacerbations and decreased after antibiotic therapy. CONCLUSION: Plasma sialic acid and pHLE complexes reflect clinically meaningful changes in CF lung disease. In contrast, plasma cytokine levels did not correlate with lung function.

Coupling to polymeric scaffolds stabilizes biofunctional peptides for intracellular applications.

Here, we demonstrate that coupling to N-hydroxypropyl methacrylamide (HPMA) copolymer greatly enhances the activity of apoptosis-inducing peptides inside cells. Peptides corresponding to the BH3 domain of Bid were coupled to a thioester-activated HPMA (28.5 kDa) via native chemical ligation in a simple one-pot synthesis. Peptides and polymer conjugates were introduced into cells either by electroporation or by conjugation to the cell-penetrating peptide nona-arginine. The molecular basis of the increased activity is elucidated in detail. Loading efficiency and intracellular residence time were assessed by confocal microscopy. Fluorescence correlation spectroscopy was used as a separation-free analytical technique to determine proteolytic degradation in crude cell lysates. HPMA conjugation strongly increased the half-life of the peptides in crude cell lysates and inside cells, revealing proteolytic protection as the basis for higher activity.

Geographical range of Rio Mamoré virus (family Bunyaviridae, genus Hantavirus) in association with the small-eared pygmy rice rat (Oligoryzomys microtis).

Hantavirus HTN.007 was originally isolated from a small-eared pygmy rice rat (Oligoryzomys microtis) captured in northeastern Peru. The results of analyses of nucleotide and amino acid sequence data in this study indicated that HTN.007 is a strain of Rio Mamoré virus (RIOMV) which is enzootic in small-eared pygmy rice rat populations in Bolivia. As such, the results of this study extend our knowledge of the geographical range of RIOMV and support the notion that the small-eared pygmy rice rat is the principal host of RIOMV.

Exploiting enzymatic promiscuity to engineer a focused library of highly selective antifungal and antiproliferative aureothin analogues.

Aureothin is a shikimate-polyketide hybrid metabolite from Streptomyces thioluteus with a rare nitroaryl moiety, a chiral tetrahydrofuran ring, and an O-methylated pyrone ring. The antimicrobial and antitumor activities of aureothin have caught our interest in modulating its structure as well as its bioactivity profile. In an integrated approach using mutasynthesis, biotransformation, and combinatorial biosynthesis, a defined library of aureothin analogues was generated. The promiscuity of the polyketide synthase assembly line toward different starter units and the plasticity of the pyrone and tetrahydrofuran ring formation were exploited. A selection of 15 new aureothin analogues with modifications at the aryl residue, the pyrone ring, and the oxygenated backbone was produced on a preparative scale and fully characterized. Remarkably, various new aureothin derivatives are less cytotoxic than aureothin but have improved antiproliferative activities. Furthermore, we found that the THF ring is crucial for the remarkably selective activity of aureothin analogues against certain pathogenic fungi.