The pregnane X receptor (PXR) regulates the metabolism of many xenobiotic and endobiotic substances. In consequence, PXR decreases the efficacy of many small-molecule drugs and induces drug-drug interactions. The prediction of PXR activators with theoretical approaches such as machine learning (ML) proves challenging due to the ligand promiscuity of PXR, which is related to its large and flexible binding pocket. In this work we demonstrate, by the example of random forest models and support vector machines, that classifiers generated following classical training procedures often fail to predict PXR activity for compounds that are dissimilar from those in the training set. We present a novel regularization technique that penalizes the gap between a model’s training and validation performance. On a challenging test set, this technique led to improvements in Matthew correlation coefficients (MCCs) by up to 0.21. Using these regularized ML models, we selected 31 compounds that are structurally distinct from known PXR ligands for experimental validation. Twelve of them were confirmed as active in the cellular PXR ligand-binding domain assembly assay and more hits were identified during follow-up studies. Comprehensive analysis of key features of PXR biology conducted for three representative hits confirmed their ability to activate the PXR. CYP3A4, as well as aldehyde dehydrogenases, multidrug resistance efflux pumps, glutathione S-transferases, sulfotransferases, and transporters such as ATP binding cassette efflux transporters  (Promega) was used.® , as described previously  was added to allow for normalization.24 h after transfection, cells were treated with chemicals. After a further 24 h, cells were lysed, and Firefly and Renilla luciferase assays were performed as described previously . All traThe NucleoSpin RNA kit  was used to prepare total RNA from chemically treated differentiated HepaRG cells. Integrity of the isolated RNA was analyzed by formaldehyde-agarose gel electrophoresis. cDNA was synthesized as described previously .Relative quantification analyses (ΔΔCt) were conducted in technical triplicates with TaqMan RT-PCR using the BioMark HD system and Flex Six Gene Expression Integrated Fluidic Circuits , as described previously . TaqMan For the purpose of model development and testing, sets of compounds with measured PXR activation data were retrieved from the PubChem Bioassay database, the ToxCast database, and the literature (In terms of molecular scaffolds (described as Murcko frameworks), the PXR data sets cover in the range of 3 to 4% of the scaffolds observed in the approved drug set, 5 to 22% of the scaffolds observed in cosmetics, and 7 to 25% of scaffolds observed in pesticides . It is nIn order to obtain a better understanding of the molecular diversity of the individual PXR data sets we performed a dimensionality reduction and projection onto a 2D surface with Uniform Manifold Approximation and Projection  . UMAP laBased on these observations, we selected the PubChem PXR data set as the training set for machine learning. Not only does this data set cover the chemical space spanned by all data sets but it also is the largest consistent PXR data set available in the public domain . Henceforth, we refer to the PubChem PXR data set as the training set for ML. The ToxCast and the literature PXR data sets served as test sets. From these test sets we removed any compounds present in the training set (based on InChI representations). This reduced the ToxCast PXR data set by 393 compounds down to 768 compounds and the literature PXR data set by 39 compounds down to 370.k = 5 is the number of folds in the cross-validation, and A total of six binary models for the prediction of PXR activators and non-activators were optimized and trained on the PubChem PXR data set. These models result from the combination of two ML algorithms  with three sets of molecular descriptors , fingerprints (FPs), and the combination of both). The hyperparameters of the individual models see  were optDuring cross-validation we observed a high discrepancy between training and validation performance for all models. Our aim was to develop models that perform well also on unseen data and hence are able to identify PXR activators that are structurally distinct to those represented by the training data. In order to identify the best model, we devised a scoring function that takes both CV performance and the generalization capabilities of a model into account:The ToxCast and literature PXR data sets serve as two different test sets, each demonstrating a distinct setup. As described above, the ToxCast and PubChem PXR data sets show a highly similar distribution of compounds and scaffolds. This indicates that these two data sets fulfill the iid condition that is sufficient for an ML model to successfully learn a structure-activity-relationship on the training set that can be transferred to the test set. However, the literature PXR data set differs from the PubChem PXR data set to a degree that both data sets can be assumed to originate from different generating distributions.For each of the six types of classifiers, we selected the model that maximizes the new scoring function in the hyperparameter search  we created a subset St of the test set that includes all molecules with a maximum similarity of at most t. Using the RF model based on molecular fingerprints as an example, we computed the MCC score on all subsets of each test set as shown in We investigated the impact of the different feature sets and individual features on model performance. As shown in The in-stock collection of the MolPort database, containing 7,233,399 compounds, was screened for new potential PXR activators with the model that showed the best performance on unseen data . We henceforth refer to this model as the guiding model. All five other models optimized with gap penalization were used to create a consortium of models supporting decision making.High confidence in predictions: Any selected compound must be predicted as a PXR activator by all of the three RF and three SVM models.Novelty: The selected compounds must be structurally distinct to any known PXR ligands. This means that, at the time of selection, chemical structure similarity searches with CAS Scifinder did not result in the retrieval of any known, structurally related PXR ligands. More specifically, a minimum similarity threshold of 70 was used for the searches in CAS Scifinder, meaning that the platform would report literature even for rather distantly related PXR agonists.Purchasability: The selected compounds must be available from MolPort in sufficient quantities (5 mg) and at moderate costs.The virtual screening resulted in a rank-ordered list of compounds. From the top-ranked positions of this list we selected a total of 31 compounds for purchasing and experimental validation , taking Among the 31 selected compounds are a cluster of 11 diphenylamines (“cluster A”) and a cluster of 10 chrysanthemic acid esters (“cluster B”). Five of the chrysanthemic acid esters are characterized by a 4-{methyl}benzyl substituent.The selected compounds were tested for their ability to bind to PXR using the cellular mammalian two-hybrid PXR ligand binding domain (LBD) assembly assay , which c9 and 11) showed moderate activity in the PXR-LBD assembly assay, with 33% activation by both compounds. The other compounds of this cluster were inactive with activity of less than 10%). Compounds 9 and 11 are characterized by more bulky, hydrophobic alkyl or aryl substituents in ortho position of one of the benzene moieties.Two of the eleven compounds of the diphenylamine cluster (13 (28%) and 15 (26.5%), both characterized by nitrogen-rich, five-membered heteroaromatic rings, and 18 (40%) and 17 (45%), both characterized by a substituted 4-{methyl}benzyl moiety. Thiazolidin-4-one-derivatives have been previously reported as potent agonists of the constitutive androstane receptor (CAR) [Within the cluster of chrysanthemic acid esters, four compounds showed activity in the PXR-LBD assembly assay: or (CAR) .22 and 25 were identified as most promising in the PXR-LBD assembly assay, with activities of 137% and 91%, respectively.Among the singleton  hits, 22 almost reached the activity level of rifampicin and 25 even exceeded the activity induced by rifampicin.Overall, twelve of the selected compounds showed at least weak activity (>10% activation in comparison to rifampicin). Compound 17, 22 and 25.In order to further investigate the influence of molecular structure on compound activity in the PXR-LBD assembly assay, we purchased analogs of the most interesting compounds, 25, the initial hit (25) and 34 exhibited the highest activities in the PXR-LBD assembly assay (25) by a 4-phenyl-3,6-dihydropyridine moiety (37) led to the abolishment of the biological activity.Among the compounds structurally related to ly assay . From th25, in the case of 22, the testing of analogs  resulted in the identification of three compounds  that were more potent than the initial hit .The follow-up on the benzylidenethiazolidinone 3 and 57 . Neither25, 42 and 53. Compound 25 is the strongest tested effector of its kind. Compound 42 is the second-strongest effector of its class .Nuclear receptor LBD assembly assays do not discriminate between agonists and antagonists, which both result in LBD assembly . In orde42 was as efficient as rifampicin, 25 and 53 demonstrated reduced capacity to release the co-repressor. 42 and 53 showing reduced recruitment. These results add further evidence that the compounds act as PXR agonists.First, we analyzed the capacity of the selected compounds to modulate the interaction of PXR with co-factors, using mammalian two-hybrid assays. Similarly to rifampicin, all novel PXR effectors resulted in the release of co-repressor NCOR2 from PXR and, by that, demonstrated agonist activity A. While CYP3A4 enhancer/promoter reporter gene by compound treatment in cells with stable PXR overexpression. CYP3A4 reporter by the novel compounds was weaker than by rifampicin. Dependency on PXR was demonstrated unequivocally by co-treatment with the specific PXR antagonist SPA70 [42, as compared to 10 µM, might result from beginning cytotoxicity in H-P cells  and 0.1027, respectively, failed to reach statistical significance. Thirdly, we analyzed the induction of endogenous PXR target gene expression by compound treatment of differentiated HepaRG hepatocytes. ABCB1, CYP2B6, and CYP3A4. In contrast, 25 and 53 demonstrated induction of CYP2B6 and CYP3A4 only, while they did not, or only very weakly, induce ABCB1. The extent of CYP2B6 induction by the novel compounds was as high as by rifampicin, while induction of CYP3A4 tended to be weaker.Secondly, as PXR agonists have to activate the transcriptional activity of the receptor, we analyzed activation of transiently transfected st SPA70 , which cells see . Comparifampicin E. A simiCYP2B6 and CYP3A4 induction may indicate that the novel compounds may also act on the constitutive androstane receptor , of which CYP2B6 is the prototypical target gene [NR1I1) activation also results in induction of hepatic cytochrome P450 genes [NR1I2). Neither of the compounds activated VDR per se nor interfered with vitamin D activation of the receptor  mammalian two-hybrid interaction assays with co-repressor and co-activator proteins, (2) PXR-dependent reporter gene assays and (3) chemical induction experiments in differentiated hepatocytes, the representative compounds proved to act as agonists for PXR. Future research is however required to confirm direct physical interaction, i.e., ligand binding, to the receptor using a biochemical assay.Due to the large size and flexibility of the ligand binding pocket of the PXR, the discrimination of activators and non-activators is a challenging task, also for machine learning approaches. In order to improve the performance of machine learning models in PXR activator prediction, we designed a new regularization technique that penalizes the performance gap between training and validation data during the model selection in hyperparameter tuning. We deployed this technique on RF models and SVMs using fingerprint as well as physicochemical properties as the underlying training features. Whereas the regularized models showed a comparable performance on the training data, their MCC values for the test set were up to 0.21 higher than those of the baseline models. In a prospective screening experiment with the regularized models, 12 of the 31 purchased and tested compounds were confirmed in a PXR-LBD assembly assay to exhibit an activation of more than 10% of rifampicin activity, thereby indicating ligand binding to PXR. Importantly, these compounds are structurally distinct from any known PXR ligands. Hit follow-up studies resulted in a number of bioactive compounds, of which we studied three representatives, In summary, we have demonstrated the successful development and application of machine learning models to identify novel PXR activators. The presented regularization technique is widely applicable and is expected to be particularly useful when modeling targets with complex activity landscapes or training on highly biased data sets.


Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and causes exercise-induced bronchoconstriction (EIB). Indirect bronchial provocation tests (BPTs)  aid to diagnose asthma and identify EIB. Daily inhaled corticosteroids (ICS) can abolish AHR caused by indirect stimuli. Where strenuous physical exertion is integral to an occupation, identification of those at risk of EIB is important and documentation of inhibition of AHR with ICS is required before recruitment.A retrospective analysis was performed on 155 potential recruits with AHR to mannitol who underwent follow-up assessment after daily ICS treatment to determine the proportion that can abolish AHR using ICS and to determine any predictors of the persistence of AHR.n = 130) over the treatment period (mean ± SD 143 ± 72days), and it was defined as the provoking dose of mannitol to cause a 15% fall in FEV1  improved from (GeoMean) 183 to 521 mg. Compared with recruits in whom AHR was abolished with daily ICS , in those where AHR remained , baseline AHR was more severe , baseline FEV1% was lower , and they had a longer follow-up duration . Baseline FEV1% , FEV1/FVC , FEF25−75% , and airway reactivity to mannitol   predicted AHR remaining after daily ICS.Airway hyperresponsiveness was abolished in the majority (84%, Airway hyperresponsiveness to mannitol can be abolished after 20 weeks of daily treatment with ICS. Inhibition of AHR is likely due to attenuation of airway inflammation in response to ICS treatment. Increased airway reactivity and lower spirometry variables predicted the persistence of AHR. Thus, those with a slower response to daily ICS on AHR can potentially be identified at the commencement of monitoring ICS using inhaled mannitol. Airway hyperresponsiveness (AHR) is a key feature of asthma. In certain occupational settings, such as the military, AHR to mannitol is used to assess asthma and the risk of exercise induced-bronchoconstriction (EIB). Reduced airway calibre in the form of lower normal spirometry and more significant AHR (moderate to severe AHR to mannitol) predict a slower response to ICS treatment if the goal is to abolish AHR. Therefore, assessing AHR to mannitol along with spirometry prior to treatment may be useful to help predict the speed one can benefit from using daily ICS therapy, and the likelihood to abolish AHR.Airway hyperresponsiveness (AHR) is a key pathophysiological feature of asthma and is responsible for exercise-induced bronchoconstriction (EIB) . EIB comStrenuous physical exertion is integral in occupations such as in the military, police, and firefighters. Screening of individuals prior to recruitment into such professions using indirect BPT has been shown to be useful to identify those with AHR and at risk of EIB , 9. AHR We performed a retrospective analysis of occupational recruits having AHR to mannitol monitored in the presence of daily ICS. We also determined the proportions of recruits in whom AHR to mannitol was abolished and if baseline characteristics might determine persistence of AHR.Data were only included from individuals seeking employment  in the ADF or NSWPF. Data were included in the analysis where an initial mannitol BPT was positive and where reassessment of mannitol BPT occurred on one or more occasions within a 12-month period while using daily treatment with ICS. The majority of participants were talking low dose ICS which was a part of the ADF recruitment policy. This is not the policy of the NSWPF where standard doses of ICS in combination with a LABA can be used. Where more than one reassessment occurred within a 12-month period, the follow-up data were reported from the visit with the longest duration. Data were excluded where the reassessment period was >12-months or ICS treatment was not used.A retrospective review of the patient databases of the PFL at Westmead and Royal Prince Alfred Hospitals from 2005 to 2018 was performed. A review of each database was approved by the Western Sydney and Sydney Local Health District Human Research Ethics Committees, respectively.Spirometry was performed immediately before the mannitol BPT according to American Thoracic Society and European Respiratory Society criteria , and pre1 (PD15) is a measure of airway sensitivity to mannitol. The response is classified as severe if the PD15 is ≤35 mg, moderate if >35 mg to ≤155 mg, and mild if >155 mg to 635 mg. If the fall in FEV1 is <15% (no PD15), then the test is negative, indicating the absence of AHR to mannitol.The provoking dose of mannitol causing a 15% fall in FEV1 of 10% (PD10). The PD10 is associated with mild EIB and therefore the PD10 was also calculated for those that had a final fall in FEV1 of between 10 and 15% , known as the response dose ratio (RDR), was also assessed. To simplify interpretation, the RDR was multiplied by 100 (RDR100). Complete resolution of AHR would be considered to have been achieved following effective ICS treatment if the RDR100 < 1, as this threshold represents the upper limit of reactivity and a flat dose response curve that has been observed in healthy non-asthmatic subjects , as this degree of AHR has been shown to be associated with a greater degree of airway inflammation  for analysis and presented as the geometric mean (Gmean) and 95% CI. Where a 0% fall in FEV1 occurred, a fall of 0.1% was imputed to enable the calculation of RDR100. A PD15 of 635 mg was imputed when a PD15 did not occur on follow-up (interpreted as the resolution of AHR). Groups were generated based on follow-up PD15 , follow-up PD10 (noPD10 vs. PD10), and RDR100 at follow up (<1 vs. >1). Independent samples t-tests were used to assess differences between groups. Paired samples t-tests were used for within group change from baseline to the follow-up visit. Spearman's correlation was used to assess relationships between variables at baseline and at follow-up and to assess relationships between the improvements in variables at the follow-up visit. Chi-squared and Fishers exact tests were used to compare proportions within and between groups.Descriptive summaries and spirometry data are reported as mean and SD or number and percentage of the group. PD15, RDR100, FEV1 %predicted, FEV1/FVC%, and FEF25−75% %predicted) to evaluate potential predictors of persistent AHR at follow up ICS treatment visit. The area under the curve (AUC) was calculated and “optimal” thresholds were reported, corresponding to the point on the ROC curve closest to the upper left corner. To generate a prediction model for AHR remaining on follow-up, the first univariate binary logistic regression was performed on baseline variables to determine potential predictors. Variables suggestive of an association (P < 0.1) with persistent AHR were considered for multivariate logistic regression analysis, performed on these variables with a backward stepwise process.Receiver operating characteristic (ROC) curves were created for baseline variables .1 95% predicted ± 11] were within normal reference limits and the geometric mean (Gmean) PD15 represented mild AHR [Gmean (95%CI) PD15 184 mg (159 to 212)] ] .15) was achieved in most recruits [n = 130/155 (84%)] with a mean follow-up period of 136 days (15 (95%CI 2.6 to 3.4) equating to an increase of 1.6 doubling doses (DD) (95%CI: 1.4 to 1.8) (n = 42/130 (32%)] of those that abolished their PD15 had a PD10 at the follow-up visit (n = 56 (36%)] of all recruits showed complete suppression of the airway response to mannitol or a flat dose response curve, defined by an RDR100 <1 at the end of the follow-up period   . Howeverup visit . Over onor PD15) .15 Gmean (95% CI) 85 mg (55 to 132)], and these subjects still showed modest but statistically significant improvements in AHR  with ICS treatment , and moderate to severe AHR (PD15 <155 mg) at the baseline visit  were within normal reference limits, statistically significant improvements were observed in all spirometry variables in the group in which AHR was abolished  of persistent AHR on follow-up , p < 0.05] (The group of recruits with moderate-severe AHR at baseline [PDbolished . In thos < 0.05] .15 <635 mg) suggesting active EIB would still be present. This group with persistent AHR had more severe airway sensitivity (lower PD15) and reactivity (higher RDR100) to mannitol at baseline than those in whom AHR was abolished at follow-up. They also had significantly lower lung function at baseline; however, spirometry parameters did not improve. Further, this group was more likely to already be using ICS at the baseline assessment and had a longer follow-up duration, hence a longer treatment period. With daily ICS treatment, approximately one-third of recruits achieved no AHR  and this airway reactivity resolved similar to what is seen in normal non-asthmatic subjects who have no AHR. Those that achieved a flat dose response curve with ICS treatment had the mildest AHR severity and most normal lung function at baseline.In this population of occupational recruits with a past or current history of asthma and AHR to mannitol, AHR was abolished in the majority following approximately 4 months of daily treatment with ICS. Even in this population with overall normal lung function, small but significant improvements in spirometry were still observed. Improvements in spirometry were weakly associated with the attenuation of AHR to mannitol. In a small proportion of the study population, AHR persisted following daily ICS treatment. However, this group achieved a modest improvement in responsiveness to mannitol while still having significant AHR  is associated with significant sputum eosinophilia (median 8%), compared to the absence of sputum eosinophils median <2%) in those with mild AHR (>155 mg) % in thos, 24. The15) persisting in this group was small relative to those in whom AHR was abolished. These individuals may be less steroid responsive, as they had a longer treatment period and may potentially need more time on ICS to inhibit their AHR more effectively , approximately one-third (32%) of the recruits still had a PD10 on follow-up. A PD10 has been found to be associated with the presence of EIB  to a level of responsiveness seen in people without asthma was achieved in over a third (36%) of recruits (While most recruits abolished AHR to mannitol (noPDe of EIB . Thereforecruits . Demonstrecruits .1 and FEV1/FVC increased the likelihood of AHR persisting. Greater airway reactivity (higher RDR100) also increased the likelihood of AHR persisting. However, in the final multivariate model, a lower FEF25−75% reduced the likelihood of AHR persisting. Importantly, the probability of this model predicting response would likely change depending on the pre-test probability of the population to be tested. This model should be investigated further to determine if it can be validated and extrapolated to other populations, such as those with active asthma. Such a predictive capacity may assist with choosing different treatment regimens to increase the success of resolving AHR in recruits.We performed a logistic regression model that predicted the liklihood of the persistence of AHR in this predominately young adult male population. For spirometry variables, lower measurements for FEVThe main limitation of this study is that the data were collected retrospectively. Retrospective studies can introduce bias and while like other uncontrolled studies investigating ICS on AHR to indirect stimuli , 21, 25 Airway hyperresponsiveness to mannitol can be abolished with 20 weeks of daily treatment with ICS, in recruits who are seeking employment in careers that require strenuous physical exertion. This was achieved in the majority with low daily doses of ICS alone without LABA. Reduced pre-treatment spirometry variables and increased airway reactivity to mannitol predict the likelihood of an incomplete or slower response to daily ICS. Assessing AHR to mannitol with daily ICS may provide a useful objective marker to identify clinically meaningful attenuation of airway inflammation.The original contributions presented in the study are included in the article/supplementary material, further inquiries can be directed to the corresponding author.The studies involving human participants were reviewed and approved by Western Sydney and Sydney Local Health District Human Research Ethics Committees. Written informed consent for participation was not required for this study in accordance with the national legislation and the institutional requirements.CL contributed to trial design, data collection, preparation and analysis, manuscript preparation, and review. KW contributed to trial design, oversight of analysis, manuscript preparation, and review. CP contributed to data collection and manuscript review. HK contributed to trial design and manuscript review. JB contributed by supervising all aspects of the research, including the study concept and trial design, oversight of analysis, and manuscript preparation and review. All authors contributed to the article and approved the submitted version.JB receives a 10% share of royalties for the sale of Aridol after distribution to Royal Prince Alfred Hospital in countries outside Australia and owns shares in Pharmaxis Ltd. CP owns shares in Pharmaxis Ltd. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.All claims expressed in this article are solely those of the authors and do not necessarily represent those of their affiliated organizations, or those of the publisher, the editors and the reviewers. Any product that may be evaluated in this article, or claim that may be made by its manufacturer, is not guaranteed or endorsed by the publisher.


BackgroundAdherence to antiretroviral therapy (ART) among key populations like human immunodeficiency virus (HIV)-positive People Who Inject Drugs (PWID) could be challenging, especially in low and middle-income countries (LMICs). Therefore we conducted this study to assess the adherence to ART among HIV-positive PWID attending three methadone clinics in Dar es Salaam, Tanzania.MethodsA cross-sectional study was conducted at three methadone clinics in Dar es Salaam, Tanzania. Adherence to ART was measured by using pharmacy refill and patient self-report methods. Bivariate and multivariable logistic regression was performed to determine the association between dependent and independent variables. A p-value of less than 0.05 was considered to be statistically significant.ResultsOf the 180 participants, 97.2% recorded good adherence to ART as per the pharmacy refill method. However, only 66.1% of the PWID were found to adhere to ART based on the patient self-report method. Upon associating the self-report method with a viral load of >1000 copies/mL, participants were 3.37 times more likely to have missed their ART dose at least once in the last three days before their refill visit compared to those with a viral load of <1000 copies/mL .ConclusionThe adherence to ART among HIV-infected PWID attending methadone clinics was high based on the pharmacy refill method but relatively much lower based on the patient self-report method. There was a strong correlation between viral load and the level of adherence measured by the patient self-report method. In 2020, the number of people infected with HIV in Eastern and Southern Africa was estimated at 20.6 million, with approximately 30% being People Who Inject Drugs (PWID) ,2. PWID To improve the management of PWID, the first Sub-Saharan Africa opioid treatment program (OTP) clinic using methadone was established in February 2011 at Muhimbili National Hospital (MNH) in Dar es Salaam, Tanzania. A second center in Tanzania was set at the Mwananyamala Regional Referral Hospital in 2012. The third clinic was at Temeke Regional Referral hospital in the same city. HIV care and treatment center (CTC) services were later incorporated into the methadone clinics to provide services to the HIV-infected PWID via an Integrated Methadone and Antiretroviral Therapy (IMAT) program . It has A study that compared people who do not inject drugs to PWID found that the latter had markedly lower plasma HIV-1 ribonucleic acid (RNA) suppression rates. Among patients who achieved any HIV-1 RNA suppression, PWID had dramatically higher rates of viral load rebound and these differences were primarily driven by lower levels of adherence to ART among the PWID . A revieStudy setting and designThis descriptive cross-section study was conducted between April and June 2018 in all three methadone clinics in the Dar es Salaam region, Tanzania. Dar es Salaam is the largest city in Tanzania. In the 2012 Census, it was found to have a population of 4.36 million, accounting for 10 percent of the total Tanzania Mainland population . It is aStudy populationThe study population was HIV-infected PWID on ART attending methadone clinics in the Dar es Salaam region.Sampling proceduresAll HIV-infected PWID from the three methadone clinics in Dar es Salaam who were willing to participate in this study were enrolled. On the day of enrollment, the nurse counselor at the clinic approached the known HIV-positive PWID and asked for their consent to participate in this study. Before the interview was conducted, written prior informed consent was obtained from all participants.Data collectionA questionnaire was employed in data collection whereby the first part gathered information on socio-demographic characteristics and selected clinical characteristics like CD4 cell counts and viral load levels. The second part of the questionnaire was designed to collect socio-demographic and adherence data. The questionnaire was administered to all participants. Data were collected and stored in the REDCap database ,13.Assessment of adherenceAdherence to ART was assessed using a modified Swahili version of the self-reported adherence assessment tool developed by the AIDS Clinical Trial Group (ACTG) . PWID rePharmacy refill information was obtained from facilities refilling date records. Each refill period was identified as the interval between the last visit and the scheduled new dates. Refill adherence was 100% if all pills had been picked up on time during the planned refill period. Refill percent values above 100 for patients who refilled earlier than scheduled were rounded to 100 percent. The calculation was based on the cumulative sum of the days that a patient was late for ART pick-up appointments in each month over the follow-up period, divided by the total number of days overall periods between pick-up periods in the follow-up period of study, resulting in the percentage of time the patient was without medication possession.The calculation was made based on the following formula:Adherence (%) = (number of days for the pills dispensed previously - delay in days for next pickup) / number of days for the pills dispensed previously) * 100A subject was considered to have good adherence if scored a refill ≥85% and poor adherence if subjects had a refill <85%, the cut-off that was validated against viral load suppression in a previous study in the same setting .Assessment of CD4 and viral loadLatest CD4 counts and viral load data were extracted from patients' medical records. According to HIV standard treatment guidelines in Tanzania, these measurements were taken within six months prior to the enrollment in the current study. The CD4 counts and viral load were used to measure treatment outcomes. Viral load success was defined as a viral load count below 1000 copies/ml  as per tData analysisData were entered using Microsoft Excel  and analysis was done using Statistical Package for Social Sciences (SPSS) version 22 . Univariate analysis was carried out to determine the association between adherence as the dependent variable and independent variables. Variables with p < 0.05 were considered statistically significant in multiple logistic regression analysis.Ethical considerationEthical clearance was obtained from the Muhimbili University of Health And Allied Sciences ethical committee. Permission to conduct the study in the selected sites was sought from the respective hospital management. The purpose of the study was fully explained to all participants, and written consent was obtained before the interviews. Confidentiality was ensured by using unique code numbers to hide the identity of participants.A total of 180 PWID on ART were enrolled in the study, with the majority 60.0%, n = 109, from MNH. The mean age of participants was 37.6 years, ranging from 23 to 55 years old. The majority of the participants were male (62.2%). More than half (57.8%) of study participants were people with primary education levels. The ART regimen used by the majority (89.4%) of the study participants was a combination of tenofovir, lamivudine, and efavirenz (TLE)  had good adherence as per the pharmacy refill adherence measurement method. However, adherence measured by patient self-report methods was relatively lower compared to that of pharmacy refill method, whereby the proportion of participants with good adherence was 66.1% (n = 119). Figure Reasons for missing ARTAmong those who reported having missed a dose of ART in the last three days before a clinic visit, 51 (81%) provided the reasons for missing their dose Figure .The majority, 31 (60.8%), reported that they "simply forgot" to take their medication; 12 (23.3%) missed ART because they had traveled; the rest missed ART for other reasons, including a bad taste of the drugs, being arrested by police, watching football, being out of pills.Given the lower proportion of adherence measured by patient self-report, further analysis was done to identify the possible predictors of adherence to ART Table .There was a significant association between adherence levels measured by the patient self-report and viral load suggested with a p-value of 0.018 Table . The phaTo our knowledge, this is the first study in Tanzania to assess the level of adherence to ART among PWID since the incorporation of CTC services in the methadone clinics. In this study, the pharmacy refill method showed that almost all (97.2%) PWID had good adherence, while only 66.1% had good adherence to ART based on the self-report method. There was a significant association between adherence levels measured by the patient self-report and viral load suppression. The findings fall within the estimated range of PWID's level of adherence to ART of 33% to 97%, as reported by a systematic review study consisting of fifteen studies from seven countries using various methods of measuring adherence levels with the mean weighted adherence rate of 72% .The difference in levels of adherence to ART observed in the two methods employed in this study can be attributed to the fact that PWID attend methadone clinics every day. Since CTC clinics are incorporated into the methadone clinics, the patients are unlikely to miss their ART refill dates. The high level of poor adherence observed by the self-report method (33.9%) may imply that most PWID adhere to the assigned pharmacy refill dates but might not take the medications as indicated. Additionally, by the time this study was conducted, there was compensation provided to the PWID when they attended their methadone clinics which might have driven better adherence to ART based on the pharmacy refill method.The observed significant association between adherence levels measured by the patient self-report and viral load suggests that patient self-report could be a more reliable method for predicting virological outcomes in PWID over the pharmacy refill method. Similar findings have been reported elsewhere . This fiUnlike previous studies that reported a correlation between self-report adherence and CD4 counts ,18, thisIn this study, younger age was negatively associated with adherence to ART, whereby participants who had less than 30 years had poor adherence compared to those above 30 years. This finding is congruent with other reports where young age has been reported to predict poor ART adherence and viral suppression among PWID .This study found that some PWID missed ART doses in the last three days before their refill visit and the most common reason was that they "simply forgot" to take their medication, similar to a study conducted in Pakistan where the majority reported "simply forgot" as the reason for missing medicines in the last month . In contOur study may be limited due to using two ART adherence measures among the other methods such as pill count, plasma concentration measurement, and electronic monitoring systems. The study may also be limited by the number of days the patient was followed. Pharmacy refills may best be studied by averaging refill periods over at least a year internal to capture missed refills over a more extended period . AnotherThe adherence to ART among HIV-infected PWID attending the methadone clinic was high based on the pharmacy refill method but relatively lower based on the patient self-report method. The level of adherence measured by patient self-report showed a significant correlation with the virological outcome. Therefore ART adherence level measured by patient self-report is likely to form a good predictor of virological outcomes in PWID attending methadone clinics in settings where PWID are enrolled in integrated Integrated methadone and antiretroviral therapy. These findings need to be emulated with a more rigorous follow-up study over a long period to be used to identify patients in need of adherence counseling.


The study examined Covid-19 vaccinations intentions among literate Ghanaians and how it is been influenced by vaccine mistrust and the fear of the unforeseen side effects.th to 20th April, 2021. Likert-scale questions were asked regarding the knowledge, attitudes and perceptions of literate Ghanaians towards COVID-19 vaccines. Kruskal-Wallis and sample t-test were performed to ascertain the differences in vaccination intentions between key socioeconomic variables. A pairwise correlation was performed to examine the relationship between vaccination intensions and fear of the unforeseen, mistrust of the vaccine and concerns of profiteering. Finally, a binary probit regression model was fitted to examine the predictive effect of key variables on respondent’s vaccination intentions.We used cross sectional data collected from 223 respondents by means of questionnaire disseminated through social media from 16The results revealed a relatively low level of knowledge about the safety and efficacy of the COVID-19 vaccines. The sample t-test showed that males have a relatively positive attitude towards the COVID-19 vaccines than females at 5% level of significance. Mistrust of vaccine safety and efficacy have a significant negative influence on vaccination intensions at 1% significance level.This study provides the Ghanaian government and other stakeholders with useful information to aid in educational campaigns on the safety and effectiveness of the COVID-19 vaccine. More campaign efforts towards females could help increase uptake given their relatively poor attitudes towards the vaccine. The The section sought to determine the knowledge of respondents regarding the COVID-19 vaccine. Hence 5 questions related to knowledge of the existence of the vaccine in the country, the effectiveness of the vaccine, vaccination without knowledge of COVID-19 status, allergic reactions and knowledge whether vaccine boost immune system against other infectious diseases were asked. Participants were asked to indicate a “Yes”, “No” or “Don’t Know” to the statements been asked.A three-point likert scale  was used for participants to indicate the level at which they disagree or agree to 6 attitudinal questions about the vaccine. Hence statement related to vaccine safety, confidence of protection, intensions to vaccinate, need to encourage others to vaccinate among others as presented in the appendix.Another set of 4 questions on participants perception about the vaccine were asked. Participants were asked to indicate either “Yes”, “No” or “Maybe” to these statements pertaining to the perception about the side effects of the vaccine, perception about others profiteering from vaccines for financial gain other than for people’s health.The data was analyzed using Microsoft Excel 2019 and STATA 15 package. For knowledge, the maximum possible score is expected to be 5, for attitude the maximum is expected to be 6 and a maximum score of 4 for the perception variable. Following [Categorical variables were analyzed using frequencies and percentages while continuous variables were analyzed by means and standard deviation. Kruskal-Wallis test was used to test for the difference in knowledge, attitudes and perceptions between key socioeconomic variables.  indicateThe Pearson’s correlation coefficient was used to analyze the correlation between the knowledge, attitude and perceptions of participants. Finally, a binary probit model was fitted to ascertain the effect of COVID-19 knowledge and perceptions  on their vaccination intensions. Vaccination intentions  was recategorized into a binary outcome, where an individual is assigned a code of 1 if they agree that they will vaccinate without hesitations, otherwise 0.y* to be an underlying continuous latent variable that makes an individual willing to vaccinate, the latent variable could be modeled as;Since the dependent variable is dichotomous, we first assume Where X is a vector of variables that could influence vaccine hesitancy including fear of the unforeseen, mistrust and profiteering concerns.iY = 1 if y*>0 and iY = 0 if y*<0Hence The probit model is then given as;Where F is the standard normal cumulative distribution function which can be written asThe average marginal effect after the probit model was then fitted in order to interpret probabilities at which these variables affect vaccination intentions.All procedures for the study were carried out under the ethical guidelines of the University for Development Studies (UDS) research ethics and approved by the covid-19 committee before the study began. Informed consent was solicited from Participants in writing before the administration of the questionnaires.A total of 223 respondents were included in the final analysis. About 30.04% of all the respondents agreed that the vaccines were safe. Segregating by gender shows 35.29% of males and 18.57% of females agreed that the vaccines were safe. More males (40.79%) were confident of vaccine protection than females (18.57%). Meanwhile, 47.71% and 31.43% of males and females respectively indicated willingness to take the vaccine without hesitation when it is made available to them. That means that, 52.28% of males and 68.57% of females were either indifferent or not willing to vaccinate. Similarly, 45.75% of the males and 34.29% of females indicated willingness to encourage family and friends to take the COVID-19 vaccine. About 34.98% of the respondents indicated that it was possible to reduce the incidence of COVID-19 without being vaccinated and only 18.92% indicated that it was possible for one to get infected after being vaccinated.others promoting the vaccine for financial gain than people’s health’.The perception of participants towards COVID-19 vaccines is presented in On the whole, about 70.85% of the respondents perceive that the COVID-19 vaccine may have side effects. While 55.61% perceive that COVID-19 pandemic could be eradicated without vaccinations if everyone would adhere to the preventive measures. About 60.36% believe that some people in the country are profiteering from the COVID-19 vaccines, while 52.25% thinks that some people are promoting the COVID-19 vaccines for financial gain rather than health reasons.We further performed a sample t-test to examine the differences in knowledge, attitude and perception between key variables  under the study. The scores for respondents were generated for all three areas of knowledge, attitude and perceptions as presented in The average knowledge score was found to be 1.14 with a standard deviation of 1.17 suggesting that, out of the five knowledge items considered, a respondent on the average is likely to correctly respond in 1 or 2 of items suggesting some appreciable knowledge about the covid-19 vaccine. The average score for attitude was about 2.64(SD = 1.84) suggesting a low to moderate positive attitude among the respondents. Meanwhile, an average perception score of 1.28(SD = 1.06) was recorded suggesting that, on the average respondents had negative perception in 1 or 2 of the 4 perception items asked.The results show that, there was statistically significant difference in attitude towards the COVID-19 vaccines between males and females with the males recording a relatively higher (M = 2.84) positive attitude than the females (M = 2.20). Such results further confirm the earlier results in A Pairwise correlation was performed to ascertain if there was a relationship between vaccination intensions, fear of the unforeseen, mistrust of the vaccine and concerns of profiteering. The results in We further conducted a binary probit regression to examine the predictive effect of these variables and some socio-demographic variables on respondent’s vaccination intentions in Ghana. The definition of these variables and how they were measured is showed in The cross-sectional study examined vaccinations intentions of literate Ghanaians. We examined the knowledge, attitudes and perceptions of literate Ghanaians towards the covid-19 vaccines. The results showed a relatively low level of knowledge about the safety and effectiveness of the COVID-19 vaccine among the respondents. Even though about 97.30% of the respondents were aware of the presence of the vaccine in the country, they were very doubtful about the effectiveness of the COVID-19 vaccine, and felt that it was dangerous for someone to receive the vaccine without knowing his/her COVID-19 status. Over 50% of the respondents were either indifferent or did not agree that vaccines were safe or offered protection against Covid-19. This suggest a need for more sensitization and educational campaigns about the safety and efficacy of the COVID-19 vaccine if the government’s aim of vaccinating at least 60% of the population is to be achieved. In neighboring Nigeria,  also repMale respondents had a relatively higher positive attitude towards the COVID-19 vaccines than females. There was widespread misinformation on various social media platforms that taking Covid-19 vaccines could lead to women not being able to conceive or become pregnant in the future. Similar results were found in previous studies . Such reThe study found a considerably high level of negative perception about the COVID-19 vaccine among the respondents. For example, about 70.85% of the respondents perceive that the vaccines could have some hidden or unknown long-term side effects. About 60.36% of the respondents had the perception that, some people in the country were profiteering from the COVID-19 pandemic, in particular, 52.25% of the respondents indicated that some powerful individuals were promoting the vaccine for their selfish financial gains. An individual perception influences his or her actions and the relatively high negative perception about the vaccine in the country needs to be corrected in order to achieve the target of vaccinating at least 60% of the entire population.About 42.60% of the respondents indicated willingness to receive the COVID-19 vaccines without any hesitation when it is made available to them. The remaining 57.40% were either not willing or indifferent on their vaccination intentions. A pairwise correlation analysis revealed that, participant’s willingness to take the COVID-19 vaccine was negatively correlated with the fear of the unforeseen (side effects). There was a strong negative correlation between vaccination intensions and mistrust of vaccines.A binary probit model further confirmed that, mistrust of vaccines had a negative and significant effect on respondents’ vaccinations intentions at 5% level of significance. Such results suggest that respondents who did not have confidence in the safety of the COVID-19 vaccines were unwilling to take the vaccine. The probability that those who mistrusted the vaccine efficacy and less likely to take the vaccine was 67.50% more than those who trusted it ceteris paribus. Our results are consistent with that of [The study examined the literate Ghanaians vaccination intentions against COVID-19 as well as estimated the effect of mistrust of vaccines, the fear of the unforeseen future side effects and concerns about profiteering and individual vaccination intentions. Using a data collected from 223 respondents, we employing a mixed-method in the analysis. Results from the study revealed a relatively low level of knowledge about the safety and efficacy of the COVID-19 vaccines. There are some significant negative perception and attitude about the COVID-19 vaccines. Male respondents showed a relatively more positive attitude and were more likely to receive the COVID-19 vaccines than female respondents. Mistrust about the vaccine safety was found to adversely affect respondent’s vaccination intentions. There is therefore the need for the Ghanaian and civil society groups to intensify campaigns and educational messages about the safety and effectiveness of the COVID-19 vaccines approved for use in the country. This will enlighten citizenry and erase some of the wrong notions people hold about the vaccine in the country. More vaccination campaign efforts targeting females is particularly necessary to help increase uptake given the relatively poor attitudes to the vaccines compared with the males.First, the data was collected through social media platforms and there is no guarantee that participants did not search for answers from other sources which can introduce some bias. To minimize this bias, the period in which the data was taken was limited to 5 days. Also, the method in which the data was taken limited the participation of illiterates. Further research on the subject should consider increasing the sample to include both literates and illiterates.Your responses would be anonymous and confidentialWe are a team of researchers from the University for Development Studies, collecting data for purely academic purpose. The research seeks to examine the vaccination intensions among the literate Ghanaian. Questions related to the Knowledge, Attitudes and Perceptions (KAP) towards covid-19 vaccines are asked. A. DEMOGRAPHIC CHARACTERISTICSAge of respondent……………Sex of respondent Male  Female Which part of Ghana do you come from? North  South Which of the following categories does your programme of study falls under?Health Science  Natural & Agric Science  Social Science  Others What is the level of your study? Diploma  Undergraduate  Masters  PhD How often do you use the internet? Not at all  Sometimes  Most often B. COVID-19 Vaccine Related KnowledgePlease indicate Yes (Y) or No (N) or Don’t know (D) to the following statements/questionsDo you know about the COVID-19 vaccine?Do you know about the effectiveness of the COVID-19 vaccine?It is dangerous to get vaccinated without knowing your COVID-19 statusDoes vaccination increase allergic reactions?Does vaccination boost immune system against other infectious diseases?C. ATTITUDES TOWARDS COVID-19 VACCINESIndicate the level in which you agree to the following. In each case 1 = Disagree, 2 = Indifferent/undecided 3 = AgreeThe COVID-19 vaccines are safeI am confident of being protected after vaccinationI will take the COVID-19 vaccine without any hesitation if it is made available to meI will also encourage my family/friends/relatives to get vaccinatedIt is not possible to reduce the incidence of COVID-19 without being vaccinatedIt is not possible to get infected with COVID-19 after being vaccinatedD. PERCEPTIONS TOWARDS COVID-19 VACCINESDo you think the COVID-19 vaccine may have side effects? Yes  No Do you think that if everyone in the society will keep to the prevention measures, COVID-19 pandemic can be eradicated without vaccination? Yes  No Who do you think should first be vaccinated? (Select only 3)Politicians Health workers Teachers and students The Aged and people with underlying health conditions Commercial drivers General public Do you think some people in Ghana are profiteering from the COVID-19 vaccines?Yes  No Do you think some authorities are promoting vaccinations for financial gain rather than people health? Yes  No S1 File(DTA)Click here for additional data file.


For patients presenting with an aneurysmal subarachnoid hemorrhage (aSAH), delayed cerebral ischemia (DCI) is a significant cause of morbidity and mortality. The REACT study is designed to assess the safety and efficacy of clazosentan in preventing clinical deterioration due to DCI in patients with aSAH.REACT is a prospective, multicenter, randomized phase 3 study that is planned to enroll 400 patients with documented aSAH from a ruptured cerebral aneurysm, randomized 1:1 to 15 mg/hour intravenous clazosentan vs. placebo, in approximately 100 sites and 15 countries. Eligible patients are required to present at hospital admission with CT evidence of significant subarachnoid blood, defined as a thick and diffuse clot that is more than 4 mm in thickness and involves 3 or more basal cisterns. The primary efficacy endpoint is the occurrence of clinical deterioration due to DCI up to 14 days post-study drug initiation. The main secondary endpoint is the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation. Other secondary endpoints include the modified Rankin Scale (mRS) and the Glasgow Outcome Scale-Extended (GOSE) score at Week 12 post-aSAH, dichotomized into poor and good outcome. Radiological results and clinical endpoints are centrally evaluated by independent committees, blinded to treatment allocation. Exploratory efficacy endpoints comprise the assessment of cognition status at 12 weeks and quality of life at 12 and 24 weeks post aSAH.In the REACT study, clazosentan is evaluated on top of standard of care to determine if it reduces the risk of clinical deterioration due to DCI after aSAH. The selection of patients with thick and diffuse clots is intended to assess the benefit/risk profile of clazosentan in a population at high risk of vasospasm-related ischemic complications post-aSAH.ClinicalTrials.gov (NCT03585270). EU Clinical Trial Register (EudraCT Number: 2018–000241-39).The online version contains supplementary material available at 10.1186/s12883-022-03002-8. Aneurysmal subarachnoid hemorrhage (aSAH) occurs at a rate of 7.9 cases per 100,000 person-years –4. DespiHemodynamic therapy consisting of the administration of IV fluids and vasopressors is the first step in the treatment of symptomatic vasospasm . The onlThe pathogenesis of vasospasm after aSAH is thought to be initiated by clot hemolysis and the release of hemoglobin, oxyhemoglobin, and thrombin in the subarachnoid space resulting in an imbalance between vasoconstrictor (endothelin-1) and vasodilator substances (nitric oxide) , 21–23. The REACT study protocol is detailed in anticipation of the upcoming study results.The primary goal of the REACT study is to determine the efficacy of clazosentan in preventing clinical deterioration due to DCI up to 14 days post-study drug initiation. Secondary objectives include the evaluation of the effect of clazosentan on the occurrence of clinically relevant cerebral infarction at Day 16 post-study drug initiation and the impact on the long-term clinical outcome and cognition at Week 12, and on quality of life at Week 12 and 24 post-aSAH. The assessment of safety and tolerability up to 24 hours after study drug discontinuation is also a secondary objective. In addition, the study evaluates the effect of clazosentan on healthcare resource utilization.REACT is a prospective, multicenter, double-blind, randomized, placebo-controlled, parallel-group, phase 3 study. It aims to enroll 400 patients with aSAH from a ruptured brain aneurysm at approximately 100 sites  in approximately 15 countries. After randomization to clazosentan vs. placebo, patients enter a double-blind treatment period for a maximum duration of 14 days, which is followed by a safety follow-up period of 24 hours, preceding any hospital discharge. The extended follow-up period includes an on-site visit 12 weeks after the aSAH, and a telephone interview 24 weeks after the aSAH (end-of-study visit) for safety and efficacy assessments  infusion for up to 14 days with a minimum of 10 days, on top of the usual standard of care for the management of aSAH. The study drug infusion is administered in an intensive care unit in parallel to the administration of hemodynamic therapy as per the Patient Management Guidelines , a protocol deviation , a diagnostic or therapeutic procedure, a laboratory abnormality, or for administrative reasons.The usual standard of care for the management of aSAH, including oral or i.v. nimodipine, is allowed except for those therapies considered forbidden as described below. “Statins”  may only be administered if the patient was receiving them chronically for treatment of high cholesterol. Urgent endovascular rescue therapy for the treatment of refractory vasospasm  can be administered at any time during the treatment period for refractory vasospasm but requires temporary interruption of study drug. Intravenous administration of vasodilators  are allowed as rescue therapy only if preceded by intra-arterial administration of a vasodilator.Vaccines (including those for Coronavirus disease 2019 [COVID-19]) may be administered at any time during the study.The following treatments are not allowed until the primary endpoint is assessed due to their potential to interfere with the evaluation of efficacy or safety, or due to the potential for a drug-drug interaction with study drug: intra-aortic balloon device; lumbar and/or cisternal drainage for the prevention of cerebral vasospasm and/or DCI; i.v. milrinone, i.v. nicardipine (may be used for blood pressure control), and intrathecal/intra-cisternal/intra-ventricular vasodilators ; i.v. magnesium, i.v. albumin, or plasma volume expander if administered specifically for the prevention of vasospasm and/or DCI; thrombolytics (except to open an occluded drain) and antifibrinolytics; i.v. hypertonic saline ; i.v. mannitol (in the absence of brain edema or high ICP); strong inhibitors of organic anion transporting polypeptide (OATP)1B1 and OATP1B3 transporter proteins; other endothelin receptor antagonists; any investigational drugs, procedures, or devices; traditional medicines.The primary efficacy endpoint ) is the occurrence of clinical deterioration due to DCI, from study drug initiation up to 14 days post-study drug initiation. Clinical deterioration due to DCI is defined as a worsening of at least 2 points on the modified Glasgow Coma Scale (mGCS) or the abbreviated National Institutes of Health Stroke Scale (aNIHSS), lasting for at least 2 hours, which cannot be entirely attributed to causes other than cerebral vasospasm  the primary endpoint is assessed based on the totality of available clinical data.3 or cerebral infarction < 5 cm3 in patients with clinical deterioration due to DCI. This definition was updated following protocol amendment  and the Independent Radiology Committee (IRC) data (for infarct size).Cerebral infarction refers to new or worsened infarcts and is determined by central radiology review, comparing the total volume of infarcts on the CT scan performed 16 days after study drug initiation with the total volume on the CT scan performed just prior to randomization. If the CT scan cannot be performed on Day 16, then it is acceptable for the CT to be performed within 7 days following Day 16. If a patient is discharged from the hospital prior to Day 16, the CT scan is performed on the day of hospital discharge. Clinical deterioration due to DCI and cerebral infarctions ≥ 5 cmOther secondary endpoints include long-term clinical outcome, assessed at Week 12 post-aSAH by the modified Rankin scale (mRS)  dichotomExploratory endpoints include cognitive status assessed with the Montreal Cognitive Assessment .3 in total volume  and the Oxford Participation and Activities Questionnaire . Quality of life is also evaluated with the Stroke Specific Quality of Life .The pharmaco-economic endpoints describe the number and type of episodes of rescue therapy, and the number and type of specific medical treatments and therapies from randomization up to hospital discharge and from hospital discharge up to Week 12 post-aSAH. The length of initial and total intensive care unit stay, the length of total hospitalization, and duration in different hospital/institutional care units are recorded from randomization up to hospital discharge and from hospital discharge up to Week 12. The intensity of rehabilitation care up to Week 12 post-aSAH, the first post-hospital discharge location, and the duration of home care support post-initial hospital discharge are documented. The employment status is collected at Week 24 post-aSAH.The area under the plasma concentration-time curve of the S100b protein from baseline to Day 10 and 14 post-study drug initiation is to be calculated. The S100b protein has emerged as a brain ischemia biomarker that is implicated in the pathogenic process of aSAH .The safety endpoints include the occurrence of treatment-emergent adverse events (TEAEs), serious TEAEs, TEAEs of specific interest , and treatment-emergent marked laboratory abnormalities up to 24 hours after study drug discontinuation . TEAEs leading to premature discontinuation of study drug and death  up to week 24 post-aSAH are to be collected. The occurrence of rescue therapy-specific adverse events up to hospital discharge  is also documented.An overview of the timing of the assessments is presented in Table The GCS , body temperature, fluid balance, electrocardiogram parameters, laboratory test results are collected according to the schedule provided in Table Four null hypotheses are tested according to a fixed sequence procedure  at the two-sided significance level of 0.05 until first non-rejection.The primary statistical analysis is performed on the full analysis set, which includes all patients from the randomized analysis set who have started the study treatment. This is in accordance with the intention-to-treat principle as a) randomized but untreated patients are rare and b) the decision whether or not to begin treatment cannot be influenced by knowledge of the assigned treatment. The primary endpoint is analyzed using a Cochran-Mantel-Haenszel test, stratified on WFNS grade (1–2 versus 3–5) and age at hospital admission (≤ 60 and > 60 years). The treatment effect (clazosentan versus placebo) is expressed in terms of odds ratios and also in terms of relative risk reduction of the active arm compared to placebo with corresponding 95% confidence limits.Supportive analyses include logistic regression to estimate the treatment effect after adjusting for WFNS grade and age at hospital admission. Subgroup analyses are conducted for WFNS grade and age at hospital admission.Similar analyses are performed for the primary and secondary efficacy endpoints.The safety analysis provides descriptive statistics for each treatment arm.No interim analyses are planned in this study.2 test with a 5% two-sided significance level. When taking an approximate 10% drop-out rate into account, 400 patients have to be enrolled in the study, with 200 patients randomized to each treatment arm.The sample size is derived from the assumption that the true incidence of clinical deterioration due to DCI up to 14 days after study drug initiation is 28% in the placebo arm and 14% in the clazosentan arm ; a samplThe CEC provides a final assessment (yes or no) on the primary endpoint, indicating for each patient whether it has been met, therefore it is assumed that there are no missing data for the primary endpoint. In addition, the CEC distinguishes between the cases of clinical deterioration due to DCI and the cases imputed according to the substitution rules described for the primary endpoint.3), indicating for each patient whether it has been met and distinguishing between the true cases of cerebral infarction ≥ 5 cm3 and imputed cases (as per CEC charter). Regarding the second component, patients who met the primary endpoint as per CEC but with missing CT scan at Day 16 are considered to have met the secondary endpoint .The CEC provides a final assessment (yes or no) on the first component of the main secondary endpoint  at day 16 post-study drug initiation. The latter is to be analyzed as an exploratory endpoint. The mRS was formally included in the statistical hierarchical testing strategy, just before the GOSE.Changes to the protocol occurring after study start are listed in Additional file As a consequence of the Coronavirus disease 2019 (COVID-19) declared a pandemic by the World Health Organization (WHO) on 11 March 2020, Idorsia put the recruitment for the REACT study on hold temporarily, on 19 March 2020.All protocol deviations related to the COVID-19 crisis are to be identified and tracked. This will allow, at the end of the trial, a reconstruction of the impact that such deviations had on the trial integrity and interpretability.In case of logistical restrictions due to the COVID-19 pandemic, it is possible to postpone the Week 12 assessments up to Week 24 (at the latest) and to perform the safety follow-up of ongoing adverse event in an alternative hospital or local laboratory. It is reminded that if OATP inhibitors are used  then study drug must be permanently discontinued as per study protocol. It is possible to perform remote monitoring and source data verification if allowed locally, otherwise alternatives may be agreed with the principal investigator to ensure data integrity.An Independent Data Monitoring Committee is responsible for monitoring unblinded safety and efficacy data at regular intervals.An Independent Radiology Committee (IRC) composed of radiologists, who are independent from the study sponsor and blinded to treatment allocation, review all angiograms and CT scans to document and quantify specific radiological findings including clot size, cerebral vasospasm, and cerebral infarction.3 based on the central review of CT scans performed by the IRC or other available data when the CT scan is missing at day 16 post-study drug initiation. Cerebral infarcts < 5 cm3 in patients with clinical deterioration due to DCI are derived from both the CEC data (primary endpoint) and IRC data (for infarct size).An Independent Clinical Event Committee (CEC) composed of clinicians with expertise in aSAH, who are blinded to treatment allocation, determine whether the primary endpoint and the main secondary endpoints have been met. This committee reviews clinical and imaging data from all patients to determine which cases fulfill the definition of clinical deterioration due to DCI. It also adjudicates cases for the presence of a new or worsened cerebral infarct ≥ 5 cmCommittee charters are available from the corresponding author upon reasonable request once trial results are published.Data from source documents are reported in the patient electronic case report form using electronic data capture. Results from laboratory analyses are electronically sent to the sponsor. Adverse events and medical history are coded according to the latest Medical Dictionary for Regulatory Activities (MedDRA™) version used by the sponsor. Medications are coded according to the latest WHO Drug Dictionary version used by the sponsor.All data and documentation related to the trial are stored on site for as long as is necessary to comply with the sponsor’s requirements and national and/or international regulations. Access to data is restricted to authorized trial personnel.The sponsor representatives may audit the investigator site.The planned recruitment of 400 patients was reached in May 2022 and the study was completed in November 2022.Delayed cerebral ischemia contributes significantly to poor outcome after aSAH  and therThe primary efficacy endpoint of the trial is the occurrence of clinical deterioration due to DCI, from study drug initiation up to 14 days post-study drug initiation. It is defined as a sustained worsening in neurological status that cannot be entirely attributed to causes other than cerebral vasospasm consistent with the recommendations of international multi-disciplinary aSAH research groups , 43. The3 are mostly related to vasospasm and have a high association with poor clinical outcome at 3 months, as compared to those with a cumulative volume less than 5 cm3 [3) only included those infarcts ≥ 5 cm3 in order to set a meaningful cut-off for infarct volume when considering all infarcts irrespective of cause. Since the determination of underlying infarct etiology based on CT scan assessment is often challenging, the 5 cm3 threshold serves as a proxy for vasospasm-related stroke. This endpoint also allowed the identification of ischemic events that are not detectable on clinical examination or that develop in patients who cannot be evaluated neurologically . However, routine blinded monitoring of the event rate during the REACT study revealed a lower-than-expected incidence of infarcts ≥ 5 cm3, resulting in insufficient power to detect a treatment effect. This led to an expansion of the endpoint definition to include cerebral infarcts < 5 cm3 if they occur in patients with clinical deterioration due to DCI. Although the infarcts < 5 cm3 have a lower association with vasospasm and prognosis, their vasospastic origin and their contribution to poor outcome cannot be completely excluded [The main secondary endpoint in the REACT study is the occurrence of clinically relevant cerebral infarction, a known complication of aSAH, which has been repeatedly shown to be a strong predictor of poor long-term clinical outcome , 55, 56.an 5 cm3 . Therefoexcluded , 59. Theexcluded .Despite being correlated with the primary efficacy endpoint, the main secondary endpoint goes beyond clinical symptoms since deterioration due to DCI does not always result in the development of cerebral infarction. Conversely, cerebral infarction may be observed on a CT scan in the absence of clinical symptoms in up to 20% of aSAH patients , 60. TheThe other secondary endpoints of the REACT study are the mRS and GOSE scores at Week 12, which assess long-term clinical outcome. These scores have been chosen as secondary, rather than primary efficacy endpoints, because they are strongly driven by the initial hemorrhage and the complications of the aneurysm treatment procedure , on whicFinally, the REACT protocol includes a series of cognitive tests and patient reported outcome tools performed at 12 and/or 24 weeks after the aSAH with the objective to capture most of the aSAH-associated long-term disability.A key feature of the REACT study is the enrolment of a selected population with a high risk of developing vasospasm-related ischemic complications. This risk is correlated with the amount of blood on the initial CT scan . Thus, tClazosentan is known to reduce the occurrence and severity of vasospasm occurring after aSAH and was recently shown to decrease the combined incidence of vasospasm-related morbidity and all-cause mortality in two phase 3 studies conducted in Japan. The ongoing REACT study further investigates whether clazosentan can prevent the clinical deteriorations due to DCI and improve long-term outcome in an enriched patient population at high risk of vasospasm-related ischemic events.Additional file 1. Trial registration data.Additional file 2. Definition of “thick and diffuse clot” on hospital admission CT scan.Additional file 3. Changes to the protocol occurring after study start.Additional file 4. Participant information and consent forms.Additional file 5. Patient Management Guidelines.Additional file 6. Glasgow Coma Scale and Modified Glasgow Coma Scale.Additional file 7. Abbreviated National Institutes of Health Stroke Scale.Additional file 8. Glasgow Outcome Scale–Extended and Modified Rankin Scale.


Food insecurity during the COVID-19 pandemic has been impacted by necessary public health restrictions. Tasmania, an island state south of the Australian mainland, recorded no community transmission of COVID-19 between May 2020 to November 2021 due to strong border restrictions. This study aimed to determine the changes in prevalence and sociodemographic predictors of food insecurity throughout the COVID-19 pandemic in Tasmania, Australia.In May 2020 (survey 1: during lockdown), September 2020 (survey 2: eased restrictions) and May 2021 (survey 3: 1-year post-lockdown), cross-sectional, online surveys using convenience sampling methods determined food insecurity in Tasmanian adults using the USDA Household Food Security Survey Module: Six-Item Short Form, in addition to key sociodemographic questions. Crude and age-adjusted prevalence of food insecurity was calculated, and binary logistic regression determined at-risk groups and changes in prevalence over time.n = 1168), 19.5% when restrictions had eased (n = 1097) and 22.6% 1-year post-lockdown (n = 1100). Young adults, Aboriginal and/or Torres Strait Islander people, individuals with disabilities, families with dependents and temporary residents were at highest risk across all time points.The age-adjusted prevalence of food insecurity was 27.9% during lockdown (The prevalence of food insecurity was higher than pre-pandemic levels across all three time points. Our results indicate the potential long-term impacts of the COVID-19 pandemic on food security in Australia, where despite easing social distancing restrictions and a lack of COVID-19 transmission, the prevalence of food insecurity reduced, but did not recover to pre-pandemic levels 1-year following a lockdown.The online version contains supplementary material available at 10.1186/s12966-022-01347-4. As defined by the Food and Agriculture Organization of the United Nations, food security is a situation that exists “when all people, at all times, have physical, social and economic access to sufficient, safe and nutritious food that meets their dietary needs and food preferences for an active and healthy life” . Food seThe pathways through which the COVID-19 pandemic has impacted food security have been well described  and inclA systematic review of food security research published in the first year of the pandemic demonstrated that the vast majority of studies reported that household food insecurity had increased and that food production and distribution was disrupted . HoweverFluctuations in the prevalence of food insecurity after the onset of the COVID-19 pandemic have been reported in the USA , showingHow did the prevalence and severity of food insecurity change between May 2020 to May 2021?Which population groups were at higher risk of food insecurity, and did these groups change between May 2020 and May 2021?Given the vastly different trajectories of the COVID-19 pandemic around the world, evidence from a range of countries and contexts is required to inform responses to future pandemics that are appropriate for each setting. To fill a critical gap in research within an Australian context, this study aimed to compare the prevalence of food insecurity at three time points over 1 year during the COVID-19 pandemic in Tasmania, Australia. The following research questions guided our study:younger adults compared with older adults due to surges in youth under- and un-employment during the pandemic;people from Aboriginal and/or Torres Strait Islander backgrounds who experience greater disadvantage ;people with a disability compared with those without a disability, related to lower income and poorer access to food;people living in rural areas compared with people living in urban areas due to supply chain challenges in rural regions;people with less than a university-level education due to lower income;temporary residents compared with citizens due to a lack of government financial protection available to this group during the pandemic; andcouple households with dependent children compared to couples without dependents due to higher expenses in these households.It was hypothesised that the prevalence of food insecurity would be highest at the beginning of the pandemic during a lockdown and significantly reduced after restrictions eased and 1-year post lockdown, but remain higher than pre-pandemic levels at subsequent timepoints (similarly to other high-income countries ). It wasTasmania is the island state of Australia sitting south of the Australian mainland, with a population of approximately 542,000 people . Due to The Tasmania Project, a longitudinal project established by the Institute for Social Change (University of Tasmania) to understand how Tasmanians are experiencing and adjusting to the social, political, and economic responses to COVID-19. In total, The Tasmania Project has conducted a series of 11 cross-sectional, online surveys since the beginning of the COVID-19 pandemic in Australia with a non-random sample of Tasmanian residents aged 18 years and over. Three surveys measured food security and have been included in this repeated cross-sectional measures analysis:Survey 1 - open from 25 May to 7 June 2020Survey 2 - open from 26 August to 6 September 2020Survey 3 - open from 29 April to 12 May 2021A series of surveys were conducted through With a recall period of the previous 30 days, Survey 1 captured experiences throughout and shortly after strict stay at home requirements , Survey 2 captured experiences several months after most restrictions had been withdrawn , and Survey 3 captured experiences approximately 1 year since the pandemic began and 4–6 weeks after a reduction in federal government financial support . An overview of these figures for each survey is provided in Table Participants were recruited to At each of the three time points, food security status was determined using the HFSSM based on a reference period of the previous 30 days . The HFSp < 0.05. Participants who did not complete the HFSSM were excluded from the analyses and participants who were missing values for a sociodemographic variable were excluded from analysis which included that variable.Data sets were exported from the online survey platform to IBM SPSS Statistics for Windows, version 26.0  and prepared for statistical analysis which was performed in Stata 14.2 . All available survey data were used in the analyses. The significance level for all analyses was set at p < 0.1. Collinearity in the multivariate model building was assessed using the Variance Inflation Factor (VIF) with a scores > 5 indicating issues with collinearity. The change in prevalence over the three time points was determined using univariate and multivariate logistic regression adjusting for age, Aboriginal and/or Torres Strait Islander status, disability status, residency status, education, household composition, and rurality.Affirmative responses to the six questions on the HFSSM  were assThe sociodemographic characteristics Table  demonstrThe crude prevalence for food insecurity according to all sociodemographic characteristics are provided in Supplementary Table The distribution of food insecurity between genders was similar at Survey 1 (26%), but higher in males at both Survey 2 and 3 , and by 19% from Survey 1 to 3 (p = 0.004). There was a non-significant increase in the prevalence of food insecurity of 16% between Survey 2 and 3, but this was not significant (p = 0.070). The multivariate analysis demonstrated the same trends. After adjusting for demographic characteristics of age, Aboriginal and/or Torres Strait Islander status, disability, residency status, education, household composition, and rurality, the odds of food insecurity were 34% lower at Survey 2 compared to Survey 1 , but the odds of food insecurity were not significantly different between Surveys 2 and 3 .Univariate regression determined that the odds of food insecurity reduced by a factor of 30% between Survey 1 and 2  , it was In our study, gender was not significantly associated with food security status, which is likely to be related to the fact that the surveys measured household food security and survey respondents were predominantly in couple households. However, our analysis shows there was a disproportionate burden in food insecurity experienced by young Tasmanians aged 18–29 years. The proportion of young people receiving unemployment payments doubled between March (5.6%) and May 11.5%) 2020, which was a higher increase than seen in other age groups and likely related to the loss of casual and temporary work during the pandemic. Our study also showed that food insecurity was substantially increased in May 2021 compared to earlier time points for this age group, which could be related to the withdrawal of the Coronavirus Supplement associated with the JobSeeker payment of which younger Australians were the primary recipients, but this requires further investigation . There w.5% 2020,In our study, lower levels of education were significantly associated with food insecurity at all time points. Education was also associated with food insecurity prior to the pandemic, however our results suggest it may have been exacerbated by this group having less access to the JobKeeper scheme, as they are more likely to be employed or be employed in casual jobs . In addiA strength of our study is that age-standardised prevalence statistics were used to more accurately indicate the extent of food insecurity across the population of Tasmania. Further, our study includes a unique assessment of how food insecurity evolved over the COVID-19 pandemic that can be used to understand the longer-term impact of the pandemic and associated public health restrictions. The limitations of the study include the use of repeated cross-sectional surveys which precludes causality inferences, and the use of convenience sampling methods which may result in a response bias and limit the generalizability of our findings. As our surveys were online and in English, this may have resulted in a sample bias towards higher-literacy respondents with internet access. Despite standardising our estimates of food insecurity by age, our sample was overall more highly educated than the wider Tasmanian community, which may result in an underestimation of food insecurity given that education is protective against food insecurity . The selIn conclusion, our study determined the impact of the COVID-19 pandemic on the prevalence of food insecurity over 1 year in a sample of adults in Tasmania, Australia. Our results suggest that the prevalence of food insecurity was substantially increased at the beginning of the COVID-19 pandemic during a lockdown, and that the prevalence did not return to pre-COVID-19 levels 1 year after lockdown and when most public health restrictions had eased. Our results also suggest there may be long-term impacts of food insecurity for communities experiencing a high burden of COVID-19 infections or those which have experienced extended periods of strict public health restrictions such as lockdowns. Further, an increase in food insecurity after the withdrawal of government financial payments introduced because of COVID-19 suggests that young Australians may be particularly reliant on this support to afford food. The increased experience of food insecurity that we have described in this study is unlikely to return to pre-pandemic levels without intervention, such as targeted food solutions to support longer-term economic recovery for vulnerable groups such as young adults, temporary residents and families with dependent children. It is apparent that a transition from reliance on emergency food relief to community led, driven and owned food solutions is a priority in an attempt to avoid the statistics in our study from becoming the “new normal” for food insecurity in Tasmania, Australia. Consumers in this region who were affected by food supply chain disruptions during the pandemic have identified that multiple strategies to build resilience in the Tasmanian food supply should be a priority to maintain food security . This inAdditional file 1: Supplementary Table 1. Crude food insecurity prevalence statistics according to all demographic characteristics collected across the three surveys showing the n (%) of each row at the three timepoints ; and the n(%) of each row classified as food insecure at each timepoint (food insecure column). Supplementary Table 2. Association between demographic factors and food insecurity—multivariate logistic regression. .


Acetabular fractures pose high demands on the surgeon and in the case of osteosynthetic treatment, anatomical reconstruction has the highest priority to achieve a good outcome. However, especially in older patients with poor bone quality, even anatomical reconstruction is no guarantee for a good clinical outcome and may nevertheless end in early osteoarthritis. Primary arthroplasty therefore has an increasing importance in the treatment of these patients. The aim of this study was to biomechanically compare fracture gap displacement and failure load as an assessment measure of the primary stability of conventional plate osteosynthesis with the treatment using a sole multi-hole cup for acetabular fractures.Six hemi-pelvises each with anterior column and posterior hemi-transverse (ACPHT) fracture were treated with either plate osteosynthesis or a multi-hole cup. The tests were carried out in a standardised test set-up with cyclic loading in various stages between 150 N and 2500 N. The fracture gap displacement was recorded with optical 3D measuring and the failure load was determined after the cyclic measurement.With increasing force, the fracture gap displacement increased in both procedures. In each group there was one treatment which failed at the cyclic loading test and a bone fragment was broken out. The primary stability in arthroplasty was comparable to that of the standard osteosynthesis.The results found seem promising that the primary arthroplasty with a sole multi-hole cup and corresponding screw fixation achieves an initial stability comparable to osteosynthesis for typical ACPHT fractures. However, further clinical studies are needed to prove that the cups heal solidly into the bone. Acetabular fractures pose a great challenge to the surgeon and require anatomical reduction for a good clinical outcome , 2. CurrTherefore, the primary arthroplasty of acetabular fractures in elderly is increasingly discussed to avoid unnecessary secondary interventions , 11, 12.But so far, it should be critically considered if the sole arthroplasty is stable enough or if an additional plate osteosynthesis is required. Noteworthy, in the majority of cases two surgical approaches are needed for arthroplasty with additional plate osteosynthesis probably increasing the risk for surgical site infection , 14. ForHowever, it remains unclear if "standard" cups with various possibilities of screw connection may provide enough stabiltiy for osteointegration within the osteoporotic bone.Here, we compared plate osteosynthesis to multi-hole acetabular cup implementation treating anterior column and posterior hemi-transverse (ACPHT) acetabular fracture in terms of fracture gap displacement and failure load as an assessment measure of primary stability.th generation composite, Pacific Research Laboratories, Inc., Vashon, WA, USA) and the same batch number were used in this study. They have an advantage of standardization in construct behavior and ensure the homogeneity of the samples. Therefore, a number of 6 per group is sufficient. The samples were embedded in casting resin  and aluminium hydroxide ) at the posterior iliac spine with an embedding construction and a template. The embedding served as a fixation point for the testing machine so that the load applied by the machine happened to be anatomically correct and reproducible. The corresponding orientation of hip bones and the force vector of the maximum load during walking are based on literature and the publication by Bergmann et al. ..17].In group 1 a bipolar head was used for force application and in group 2 a 32 mm ceramic head with matching polyethylene inlay was used for the examination of the multi-hole cups.Many studies advocate early full loading to counteract physical and mental degradation and most elderly patients are unable to perform a postoperative partial weight-bearing therapy –23. TherSeveral markers with speckle patterns were placed on each fracture fragment to measure the displacement in the fracture gaps . The fraThe analysis of the displacement between marker 1 and 2, 1 and 3, 2 and 3, and 4 and 5 was determined using the correlation software Istra 4D  and a self-developed MATLAB routine (MATLAB (R2020b), MathWorks, Natick, USA).The failure test was performed using a path-controlled test at a speed of 0.2 mm/s. In case bone fragments or the corresponding implant failed out or the force exerted by the testing machine dropped by 300 N, the test was stopped and the maximum achieved force was documented.Statistics were calculated using SPSS 24.0 for Windows® . To verify the effect of fracture displacement on osteosynthesis and arthroplasty, the data was first tested for normal distribution using the Shapiro-Wilk test and then tested on significance with the non-parametric Mann-Whitney-U test, because the samples are not normally distributed and unconnected. All statistical procedures were performed with a significance level of α = 0.05.In each of the two groups, one sample failed at the highest cyclic load level of 2500 N. The specimen of the osteosynthesis group failed after 2300 cycles and the other one of the multi-hole cup treatment failed at cycle 2010. In 2/6 samples of group 1 the force caused minor fractures at the acetabular rim.The maximum fracture gap displacement increased in both groups with increasing load in all fracture gaps examined.The comparison of the two groups demonstrates that the average increase of the maximum displacement between marker 1 and marker 2 and between marker 2 and 3 is smaller in experimental group 1 than in group 2 (p<0.01) .The displacement in the fracture gap between marker 1 and marker 3 of the two experimental groups was equal (p = 0.067). In contrast, the average fracture gap displacement between marker 4 and marker 5 was higher in osteosynthesis at the first two loading stages and in the further course the displacement was higher in the multi-hole cups group (p = 0.72).The maximum load at failure testing was comparable for the multi-hole cup (4396.6 N ± 1130.8) and for osteosynthesis (3510.7 N ± 564.1) (p = 0.173) .The present biomechanical study compares the primary stability of a classical treatment of ACPHT acetabular fractures using plate osteosynthesis with the primary arthroplasty using a multi-hole cup.For our study, a multi-hole cup was deliberately chosen that can be implanted via a direct lateral access, including the screw positions selected in our setup . CompareWe decided to test the ACPHT fracture as this is one of the most common acetabular fracture in old patients following low energy trauma . HoweverIn contrast to the present study it must be emphasized that not all studies used an experimental set-up with an anatomical force vector in the sense of a single-legged stand , 24, 25.In addition to the generally known limitations of biomechanical testing, the simulation of the one-legged stance with maximum force while walking must be viewed critically. There is always the same force application considered without any change of the force vectors, as they occur e.g. when sitting.Furthermore, the two fractures that occurred at the acetabular rim may indicate that there was a difference in the force application between the bipolar-head on the native joint and the ceramic head that applies the load through the implanted cup.As expected and shown by other biomechanical studies, fracture gap motion increased under increasing load in all hemi-pelvises independent of the treatment.The results reveal an advantage of plate osteosynthesis for the fracture gap displacement. Nevertheless, the primary arthroplasty with multi-hole cups seems to be at least equal in the comparison of the maximum failure force. The presented results obtained comparable values of failure load as Busuttil et al. published for the stability of percutaneous screw fixation and plate osteosynthesis in ACPHT acetabular fractures . AlthougNevertheless, we consider the present results to be promising. The aim of treatment for elderly patients with acetabular fracture should always be the rapid implementation of full weight bearing and the minimization of surgical approach related morbidity.This may be achieved by primary arthroplasty and should be improved by technical advancements, if possible via an isolated surgical approach. Looking ahead, implant developments with different screw options specifically adapted for fracture treatment and bone-integrating surfaces are certainly useful in this context.Despite the limitations, the present results seem promising that primary THA without additional osteosynthesis is an option of therapy if good anchorage is available. Primary stability seems comparable in the treatment of ACPHT fractures. However, clinical studies would have to be connected to verify this in terms of functional outcome and pain. The developed test setup delivered reliable results. Due to the setup, experiments with human donor preparations could be carried out.S1 Table(XLSX)Click here for additional data file.S2 Table(XLSX)Click here for additional data file.S3 Table(XLSX)Click here for additional data file.