21 research outputs found
Different gut microbial communities correlate with efficacy of albendazole-ivermectin against soil-transmitted helminthiases
Soil-transmitted helminth infections represent a large burden with over a quarter of the world's population at risk. Low cure rates are observed with standard of care (albendazole); therefore, a more effective combination therapy (albendazole and ivermectin) is being investigated but showed variable treatment efficacies without evidence of intrinsic parasite resistance. Here, we analyzed the microbiome of Trichuris trichiura and hookworm-infected patients and found an association of different enterotypes with treatment efficacy. 80 T. trichiura-infected patients with hookworm co-infections from Pak-Khan, Laos, received either albendazole (n = 41) or albendazole and ivermectin combination therapy (n = 39). Pre-/post-treatment stool samples were collected to monitor treatment efficacy and microbial communities were profiled using 16S rRNA gene sequencing, qPCR, and shotgun sequencing. We identified three bacterial enterotypes and show that pre-treatment enterotype is associated with efficacy of the combination treatment for both T. trichiura (CRET1 = 5.8%; CRET2 = 16.6%; CRET3 = 68.8%) and hookworm (CRET1 = 31.3%; CRET2 = 16.6%; CRET3 = 78.6%). This study shows that pre-treatment enterotype enables predicting treatment outcome of combination therapy for T. trichiura and hookworm infections.Trial registration: ClinicalTrials.gov, NCT03527732. Registered 17 May 2018, https://clinicaltrials.gov/ct2/show/NCT03527732
Praziquantel meets Niclosamide: A dual-drug Antiparasitic Cocrystal
In this paper we report a successful example of combining drugs through cocrystallization. Specifically, the novel solid is formed by two anthelminthic drugs, namely praziquantel (PZQ) and niclosamide (NCM) in a 1:3 molar ratio, and it can be obtained through a sustainable one-step mechanochemical process in the presence of micromolar amounts of methanol. The novel solid phase crystallizes in the monoclinic space group of P21/c, showing one PZQ and three NCM molecules linked through homo- and heteromolecular hydrogen bonds in the asymmetric unit, as also attested by SSNMR and FT-IR results. A plate-like habitus is evident from scanning electron microscopy analysis with a melting point of 202.89 °C, which is intermediate to those of the parent compounds. The supramolecular interactions confer favorable properties to the cocrystal, preventing NCM transformation into the insoluble monohydrate both in the solid state and in aqueous solution. Remarkably, the PZQ - NCM cocrystal exhibits higher anthelmintic activity against in vitro S. mansoni models than corresponding physical mixture of the APIs. Finally, due to in vitro promising results, in vivo preliminary tests on mice were also performed through the administration of minicapsules size M
Thermal proteome profiling reveals Haemonchus orphan protein HCO_011565 as a target of the nematocidal small molecule UMW-868
Parasitic roundworms (nematodes) cause destructive diseases, and immense suffering in humans and other animals around the world. The control of these parasites relies heavily on anthelmintic therapy, but treatment failures and resistance to these drugs are widespread. As efforts to develop vaccines against parasitic nematodes have been largely unsuccessful, there is an increased focus on discovering new anthelmintic entities to combat drug resistant worms. Here, we employed thermal proteome profiling (TPP) to explore hit pharmacology and to support optimisation of a hit compound (UMW-868), identified in a high-throughput whole-worm, phenotypic screen. Using advanced structural prediction and docking tools, we inferred an entirely novel, parasite-specific target (HCO_011565) of this anthelmintic small molecule in the highly pathogenic, blood-feeding barber's pole worm, and in other socioeconomically important parasitic nematodes. The "hit-to-target" workflow constructed here provides a unique prospect of accelerating the simultaneous discovery of novel anthelmintics and associated parasite-specific targets
Interaction of Saturn's magnetosphere and its moons: 1. Interaction between corotating plasma and standard obstacles
Peer Reviewedhttp://deepblue.lib.umich.edu/bitstream/2027.42/95046/1/jgra20170.pd
Does computerized CT-based 3D planning of the humeral head cut help to restore the anatomy of the proximal humerus after stemless total shoulder arthroplasty?
BACKGROUND
Restoration of proximal humeral anatomy (RPHA) after total shoulder arthroplasty (TSA) has been shown to result in better clinical outcomes than is the case in nonanatomic humeral reconstruction. Preoperative virtual planning has mainly focused on glenoid component placement. Such planning also has the potential to improve anatomic positioning of the humeral head by more accurately guiding the humeral head cut and aid in the selection of anatomic humeral component sizing. It was hypothesized that the use of preoperative 3-dimensional (3D) planning helps to reliably achieve RPHA after stemless TSA.
METHODS
One hundred consecutive stemless TSA (67 males, 51 right shoulder, mean age of 62 ±9.4 years) were radiographically assessed using pre- and postoperative standardized anteroposterior radiographs. The RPHA was measured with the so-called circle method described by Youderian et al. We measured deviation from the premorbid center of rotation (COR), and more than 3 mm was considered as minimal clinically important difference. Additionally, pre- and postoperative humeral head diameter (HHD), head-neck angle (HNA), and humeral head height (HHH) were measured to assess additional geometrical risk factors for poor RPHA.
RESULTS
The mean distance from of the premorbid to the implanted head COR was 4.3 ± 3.1 mm. Thirty-five shoulders (35%) showed a deviation of less than 3 mm (mean 1.9 ±1.1) and 65 shoulders (65%) a deviation of ≥3 mm (mean 8.0 ± 3.7). Overstuffing was the main reason for poor RPHA (88%). The level of the humeral head cut was responsible for overstuffing in 46 of the 57 overstuffed cases. The preoperative HHD, HHH, and HNA were significantly larger, higher, and more in valgus angulation in the group with accurate RPHA compared with the group with poor RPHA (HHD of 61.1 mm ± 4.4 vs. 55.9 ± 6.6, P < .001; HHH 8.6±2.2 vs. 7.6±2.6, P = .026; and varus angulation of 134.7° ±6.4° vs. 131.0° ±7.91, P = .010).
CONCLUSION
Restoration of proximal humeral anatomy after stemless TSA using computed tomography (CT)-based 3D planning was not precise. A poorly performed humeral head cut was the main reason for overstuffing, which was seen in 88% of the cases with inaccurate RPHA. Preoperative small HHD, low HHH, and varus-angulated HNA are risk factors for poor RPHA after stemless TSA
Speed of recovery of the most commonly performed shoulder surgeries
Background
Shoulder surgery results in several months of rehabilitation, which is often underestimated by patients preoperatively. Currently, there is little written about this process of recovery. Information on this would help patients to anticipate the trajectory of their recovery. This would also provide a reference point allowing surgeons to compare a patient's progress in their recovery. The purpose of our study was to analyze and document the expected rate of recovery for the most common shoulder operations.
Methods
A retrospective analysis of all patients who underwent total shoulder arthroplasty (TSA), reverse total shoulder arthroplasty (RTSA), arthroscopic rotator cuff repair (ARCR), and arthroscopic biceps tenodesis (BT) using prospectively collected data from the Surgical Outcomes System registry was performed. All patients included had a complete 2-year follow-up data set. The pain score (visual analog scale) was measured preoperatively at 2, 6, and 12 weeks and 6, 12, and 24 months. The American Shoulder and Elbow Surgeons (ASES) and Single Assessment Numeric Evaluation (SANE) score were recorded preoperatively and after 6, 12, and 24 months. The speed of recovery, defined as the percentage of total improvement, for each procedure was assessed as the primary outcome parameter at all time points.
Results
All shoulder interventions resulted in significant improvement of the pain, SANE, and ASES scores 2 years after shoulder surgery. The speed of recovery of all 3 scores was highest after TSA at all measured time points and slowest after ARCR and BT. Measured by the pain score, 90% and 82% of the total improvement after TSA and RTSA was completed after 6 weeks compared to 58% and 59% after ARCR and BT, respectively. Six months postoperatively the ASES recovery rate was significantly higher after arthroplasty (TSA 96% and RTSA 85%) compared to ARCR and BT (76% and 77%, respectively). The SANE score recovery rate was between 82% and 92% (TSA 92%, RTSA 89%, ARCR 87%, BT 82%) 6 months after surgery. After 1 year all patient groups reached 89% or more of the total improvement in all scores, except for the pain after ARCR (89%).
Conclusion
The improvement in pain is fastest after TSA and slowest after ARCR and BT. After TSA and RTSA, >80% of the total pain reduction is achieved 6 weeks postoperatively, whereas after ARCR and BT, >80% of the pain reduction is achieved only 6 months postoperatively. At 12 months postoperatively, the differences in recovery curves were not significant
Phenotypic screening of histone deacetylase (HDAC) inhibitors against Schistosoma mansoni
Schistosomiasis is a prevalent yet neglected tropical parasitic disease caused by the Schistosoma genus of blood flukes. Praziquantel is the only currently available treatment, hence drug resistance poses a major threat. Recently, histone deacetylase 8 (HDAC8) selective inhibitors have been proposed as a viable treatment for schistosomiasis. Herein, we report the phenotypic screening of a focused library of small molecules of varying HDAC isozyme-inhibition profiles, including eight HDAC8 inhibitors with >10-fold selectivity in comparable functional inhibition assays and IC50 values against HDAC8<100 nM. HDAC8-selective inhibitors showed the lowest potency against Schistosoma mansoni newly transformed schistosomula (NTS). Pan-HDAC inhibitors MMH258, MMH259, and MMH373, as assessed by functional inhibition assays, with minimal or no-observed hHDAC8 and SmHDAC8 activities, were active against both NTS (MMH258, IC50 =1.5 muM; MMH259, IC50 =2.3 muM) and adult S. mansoni (MMH258, IC50 =2.1 muM; MMH373, IC50 =3.4 muM). Our results indicate that neither hHDAC8 nor SmHDAC8 activity were directly correlated to their NTS and adult S. mansoni activities