Takshan/R1 huggingface dataset:
Profiling of the anti-malarial drug candidate SC83288 against artemisinins in Plasmodium falciparum.

BACKGROUND: The increased resistance of the human malaria parasite Plasmodium falciparum to currently employed drugs creates an urgent call for novel anti-malarial drugs. Particularly, efforts should be devoted to developing fast-acting anti-malarial compounds in case clinical resistance increases to the first-line artemisinin-based combination therapy. SC83288, an amicarbalide derivative, is a clinical development candidate for the treatment of severe malaria. SC83288 is fast-acting and able to clear P. falciparum parasites at low nanomolar concentrations in vitro, as well as in a humanized SCID mouse model system in vivo. In this study, the antiplasmodial activity of SC83288 against artemisinins was profiled in order to assess its potential to replace, or be combined with, artemisinin derivatives. RESULTS: Based on growth inhibition and ring survival assays, no cross-resistance was observed between artemisinins and SC83288, using parasite lines that were resistant to either one of these drugs. In addition, no synergistic or antagonistic interaction was observed between the two drugs. This study further confirmed that SC83288 is a fast acting drug in several independent assays. Combinations of SC83288 and artesunate maintained the rapid parasite killing activities of both components. CONCLUSION: The results obtained in this study are consistent with artemisinins and SC83288 having distinct modes of action and different mechanisms of resistance. This study further supports efforts to continue the clinical development of SC83288 against severe malaria as an alternative to artemisinins in areas critically affected by artemisinin-resistance. Considering its fast antiplasmodial activity, SC83288 could be combined with a slow-acting anti-malarial drug.
Hermansky-Pudlak syndrome type 2 manifests with fibrosing lung disease early in childhood.

BACKGROUND: Hermansky-Pudlak syndrome (HPS), a hereditary multisystem disorder with oculocutaneous albinism, may be caused by mutations in one of at least 10 separate genes. The HPS-2 subtype is distinguished by the presence of neutropenia and knowledge of its pulmonary phenotype in children is scarce. METHODS: Six children with genetically proven HPS-2 presented to the chILD-EU register between 2009 and 2017; the data were collected systematically and imaging studies were scored blinded. RESULTS: Pulmonary symptoms including dyspnea, coughing, need for oxygen, and clubbing started 3.3 years before the diagnosis was made at the mean age of 8.83 years (range 2-15). All children had recurrent pulmonary infections, 3 had a spontaneous pneumothorax, and 4 developed scoliosis. The frequency of pulmonary complaints increased over time. The leading radiographic pattern was ground-glass opacities with a rapid increase in reticular pattern and traction bronchiectasis between initial and follow-up Computer tomography (CT) in all subjects. Honeycombing and cysts were newly detectable in 3 patients. Half of the patients received a lung biopsy for diagnosis; histological patterns were cellular non-specific interstitial pneumonia, usual interstitial pneumonia-like, and desquamative interstitial pneumonia. CONCLUSIONS: HPS-2 is characterized by a rapidly fibrosing lung disease during early childhood. Effective treatments are required.
Analysis of the Genetic Diversity and Population Structure of Austrian and Belgian Wheat Germplasm within a Regional Context Based on DArT Markers.

Analysis of crop genetic diversity and structure provides valuable information needed to broaden the narrow genetic base as well as to enhance the breeding and conservation strategies of crops. In this study, 95 Austrian and Belgian wheat cultivars maintained at the Centre for Genetic Resources (CGN) in the Netherlands were characterised using 1052 diversity array technology (DArT) markers to evaluate their genetic diversity, relationships and population structure. The rarefacted allelic richness recorded in the Austrian and Belgian breeding pools (A25 = 1.396 and 1.341, respectively) indicated that the Austrian germplasm contained a higher genetic diversity than the Belgian pool. The expected heterozygosity (HE) values of the Austrian and Belgian pools were 0.411 and 0.375, respectively. Moreover, the values of the polymorphic information content (PIC) of the Austrian and Belgian pools were 0.337 and 0.298, respectively. Neighbour-joining tree divided each of the Austrian and Belgian germplasm pools into two genetically distinct groups. The structure analyses of the Austrian and Belgian pools were in a complete concordance with their neighbour-joining trees. Furthermore, the 95 cultivars were compared to 618 wheat genotypes from nine European countries based on a total of 141 common DArT markers in order to place the Austrian and Belgian wheat germplasm in a wider European context. The rarefacted allelic richness (A10) varied from 1.224 (Denmark) to 1.397 (Austria). Cluster and principal coordinates (PCoA) analyses divided the wheat genotypes of the nine European countries into two main clusters. The first cluster comprised the Northern and Western European wheat genotypes, whereas the second included the Central European cultivars. The structure analysis of the 618 European wheat genotypes was in a complete concordance with the results of cluster and PCoA analyses. Interestingly, a highly significant difference was recorded between regions (26.53%). In conclusion, this is the first study to reveal the high diversity levels and structure of the uncharacterised Austrian and Belgian wheat germplasm maintained at the CGN as well as place them in a wider European context. The results should help plant breeders to utilise the most promising wheat genotypes of this study in future breeding programmes for enhancing wheat cultivars.
The dialysis orders objective structured clinical examination (OSCE): a formative assessment for nephrology fellows.

Background: Few quantitative nephrology-specific simulations assess fellow competency. We describe the development and initial validation of a formative objective structured clinical examination (OSCE) assessing fellow competence in ordering acute dialysis. Methods: The three test scenarios were acute continuous renal replacement therapy, chronic dialysis initiation in moderate uremia and acute dialysis in end-stage renal disease-associated hyperkalemia. The test committee included five academic nephrologists and four clinically practicing nephrologists outside of academia. There were 49 test items (58 points). A passing score was 46/58 points. No item had median relevance less than 'important'. The content validity index was 0.91. Ninety-five percent of positive-point items were easy-medium difficulty. Preliminary validation was by 10 board-certified volunteers, not test committee members, a median of 3.5 years from graduation. The mean score was 49 [95% confidence interval (CI) 46-51], κ = 0.68 (95% CI 0.59-0.77), Cronbach's α = 0.84. Results: We subsequently administered the test to 25 fellows. The mean score was 44 (95% CI 43-45); 36% passed the test. Fellows scored significantly less than validators (P < 0.001). Of evidence-based questions, 72% were answered correctly by validators and 54% by fellows (P = 0.018). Fellows and validators scored least well on the acute hyperkalemia question. In self-assessing proficiency, 71% of fellows surveyed agreed or strongly agreed that the OSCE was useful. Conclusions: The OSCE may be used to formatively assess fellow proficiency in three common areas of acute dialysis practice. Further validation studies are in progress.
In what circumstances could nondaily preexposure prophylaxis for HIV substantially reduce program costs?

OBJECTIVES: To review the main factors influencing the costs of nondaily oral preexposure prophylaxis (PrEP) with tenofovir (±emtricitabine). To estimate the cost reductions possible with nondaily PrEP compared with daily PrEP for different populations (MSM and heterosexual populations). DESIGN: Systematic review and data triangulation. METHODS: We estimated the required number of tablets/person/week for dosing regimens used in the HPTN 067/ADAPT (daily/time-driven/event-driven) and IPERGAY (on-demand) trials for different patterns of sexual intercourse. Using trial data, and behavioural and cost data obtained through systematic literature reviews, we estimated cost savings resulting from tablet reductions for nondaily versus daily oral PrEP, assuming 100% adherence. RESULTS: Among different populations being prioritized for PrEP, the median reported number of days of sexual activity varied between 0 and 2 days/week (0-1.5 days/week for MSM, 1-2 days/week for heterosexual populations). With 100% adherence and two or fewer sex-days/week, HPTN 067/ADAPT nondaily regimens reduced the number of tablets/week by more than 40% compared with daily PrEP. PrEP program costs were reduced the most in settings with high drug costs, for example, by 66-69% with event-driven PrEP for French/US populations reporting on average one sex-day/week. CONCLUSION: Nondaily oral PrEP could lower costs substantially (>50%) compared with daily PrEP, particularly in high-income countries. Adherence and efficacy data are needed to determine cost-effectiveness.
Multivariable risk-based patient selection for prostate biopsy in a primary health care setting: referral rate and biopsy results from a urology outpatient clinic.

Background: According to their guidelines, Dutch general practitioners (GPs) refer men with prostate-specific antigen (PSA) level ≥3.0 ng/mL to the urologist for risk-based patient selection for prostate biopsy using the Rotterdam Prostate Cancer Risk Calculator (RPCRC). Use of the RPCRC in primary care could optimize the diagnostic pathway even further by reducing unnecessary referrals. To investigate this, we calculated the risk and assessed the rate of men referred to the urologist with PSA level ≥3.0 ng/mL by implementing the RPCRC in a primary health care setting. Methods: In January 2014, an exploratory study was initiated in collaboration with the primary health care facility of the GP laboratory in Rotterdam. GPs were given the possibility to refer men with a suspicion of prostate cancer (PCa) or a screening wish to this primary care facility (STAR-SHL) where further assessment was performed by specially trained personnel. Risk-based advice on referral to the urologist was given to the GP on the basis of the RPCRC results. If requested, advice on the treatment of lower urinary tract symptoms (LUTS) was provided. All men signed informed consent. Results: Between January 2014 and September 2017, a total of 243 men, median age 64 [interquartile range (IQR), 57-70] years were referred for a consultation at the primary care facility. Of the 108 men with PSA level ≥3.0 ng/mL and a referral related to PCa, GPs were advised to refer 58 men to the urologist (54%). Of the men with available follow-up (FU) data [n=187, median FU, 16 (IQR, 9-25) months] 54 men were considered high-risk (i.e., had an elevated risk of PCa as calculated by the RPCRC). Of these men, 51 (94%) were actually referred to secondary care by their GP, and so far 38 men underwent biopsy. PCa was detected in 30 men [47% had Gleason score (GS) ≥3+4 PCa], translating to an overall positive predictive value (PPV) of 79%. Within the available FU time, 2 out of 38 (5%) men with PSA level ≥3.0 ng/mL which were considered low-risk have been diagnosed with GS 3+3 PCa. Conclusions: Risk-stratification with the RPCRC in a primary health care setting could prevent almost half of referrals of men with PSA level ≥3.0 ng/mL to the urologist. In more than three-quarters of men referred for prostate biopsy, the suspicion of PCa was confirmed and almost half of men had clinically significant PCa (GS ≥3+4 PCa). These data show a huge potential for multivariable risk-stratification in primary care.
The assessment of sperm DNA fragmentation in the saltwater crocodile (Crocodylus porosus).

Herein we report a method of assessing DNA fragmentation in the saltwater crocodile using the sperm chromatin dispersion test (SCDt) after including frozen-thawed spermatozoa in a microgel (Halomax; Halotech DNA, Madrid, Spain). Following controlled protein depletion, which included a reducing agent, sperm nuclei with fragmented DNA showed a homogeneous and larger halo of chromatin dispersion with a corresponding reduced nucleoid core compared with sperm with non-fragmented DNA. The presence of DNA damage was confirmed directly by incorporation of modified nucleotides using in situ nick translation (ISNT) and indirectly by studying the correlation of the SCDt with the results of DNA damage visualisation using a two-tailed comet assay (r = 0.90; P = 0.037). Results of the SCDt immediately following thawing and after 5 h incubation at 37°C in order to induce a range of DNA damage revealed individual crocodile differences in both the baseline level of DNA damage and DNA longevity.
Influence of model assumptions about HIV disease progression after initiating or stopping treatment on estimates of infections and deaths averted by scaling up antiretroviral therapy.

BACKGROUND: Many mathematical models have investigated the population-level impact of expanding antiretroviral therapy (ART), using different assumptions about HIV disease progression on ART and among ART dropouts. We evaluated the influence of these assumptions on model projections of the number of infections and deaths prevented by expanded ART. METHODS: A new dynamic model of HIV transmission among men who have sex with men (MSM) was developed, which incorporated each of four alternative assumptions about disease progression used in previous models: (A) ART slows disease progression; (B) ART halts disease progression; (C) ART reverses disease progression by increasing CD4 count; (D) ART reverses disease progression, but disease progresses rapidly once treatment is stopped. The model was independently calibrated to HIV prevalence and ART coverage data from the United States under each progression assumption in turn. New HIV infections and HIV-related deaths averted over 10 years were compared for fixed ART coverage increases. RESULTS: Little absolute difference (<7 percentage points (pp)) in HIV infections averted over 10 years was seen between progression assumptions for the same increases in ART coverage (varied between 33% and 90%) if ART dropouts reinitiated ART at the same rate as ART-naïve MSM. Larger differences in the predicted fraction of HIV-related deaths averted were observed (up to 15pp). However, if ART dropouts could only reinitiate ART at CD4<200 cells/μl, assumption C predicted substantially larger fractions of HIV infections and deaths averted than other assumptions (up to 20pp and 37pp larger, respectively). CONCLUSION: Different disease progression assumptions on and post-ART interruption did not affect the fraction of HIV infections averted with expanded ART, unless ART dropouts only re-initiated ART at low CD4 counts. Different disease progression assumptions had a larger influence on the fraction of HIV-related deaths averted with expanded ART.
Parental origin of deletions and duplications - about the necessity to check for cryptic inversions.

Background: Copy number variants (CNVs) are the genetic bases for microdeletion/ microduplication syndromes (MMSs). Couples with an affected child and desire to have further children are routinely tested for a potential parental origin of a specific CNV either by molecular karyotyping or by two color fluorescence in situ hybridization (FISH), yet. In the latter case a critical region probe (CRP) is combined with a control probe for identification of the chromosome in question. However, CNVs can arise also due to other reasons, like a recombination-event based on a submicroscopic, cryptic inversion in one of the parents. Results: Seventy-four patients with different MMSs and overall 81 CNVs were studied here by a novel three color FISH approach. The way how three locus-specific probes are selected (one is the CRP and two are flanking it in a distance of 5-10 Mb) enables to detect or exclude two possible parental conditions as origins of the CNV seen in the index: (i) direct parental origin of the CNV (deletion or duplication) or (ii) a parental cryptic inversion. Thus, for overall 51/81 CNVs (63%) a parental origin could be determined. 36/51 (70.5%) inherited the CNV directly from one of the parents, but 15/51 (29.5%) were due to an exclusively by three color FISH detectable parental inversion. A 2:1 ratio of maternal versus paternal inheritance was found. Also almost two times more male than female were among the index patients. Conclusion: The new, here suggested three color FISH approach is suited for more comprehensive parental studies of patients with MMS. The detection rate for parental origin was increased by 140% in this study. Still, for 30/81 cases (37%) no reason for the 'de novo' MMS in the affected index patient could be found by the here suggested FISH-probe set.
The Effect of Therapeutic Exercise on Long-Standing Adductor-Related Groin Pain in Athletes: Modified Hölmich Protocol.

Objective: The Hölmich protocol in therapeutic exercise is the most appropriate method for the treatment of long-standing adductor-related groin pain (LSAGP). Herein, we evaluated a modified Hölmich protocol to resolve the possible limitations intrinsic to the Hölmich protocol in terms of the rate of return to sport and the recovery period for athletes with LSAGP. Design: The study followed a single-blind, before/after study design, where 15 athletes with LSAGP (mean age = 26.13 years; SD = 4.48) performed a 10-week modified Hölmich therapeutic exercise protocol. Results: Outcome scores related to pain, hip adductor and abductor muscle strengths, and the ratio of maximum isometric and eccentric hip adduction to abduction strength increased significantly. Likewise, hip abduction and internal rotation ROM improved significantly compared to that at baseline. Furthermore, functional records (t-test, Edgren Side Step Test, and Triple Hop Test) showed significant improvement after treatment. Finally, 13 athletes (86.6% of the participants) successfully returned to sports activity in a mean time of 12.06 weeks (SD = 3.41). Conclusion: The findings of this study objectively show that the modified Hölmich protocol may be safer and more effective than the Hölmich protocol in athletes with LSAGP in promoting their return to sports activity. This trial is registered with  IRCT2016080829269N1.
Vaccine Induced Herd Immunity for Control of Respiratory Syncytial Virus Disease in a Low-Income Country Setting.

BACKGROUND: Respiratory syncytial virus (RSV) is globally ubiquitous, and infection during the first six months of life is a major risk for severe disease and hospital admission; consequently RSV is the most important viral cause of respiratory morbidity and mortality in young children. Development of vaccines for young infants is complicated by the presence of maternal antibodies and immunological immaturity, but vaccines targeted at older children avoid these problems. Vaccine development for young infants has been unsuccessful, but this is not the case for older children (> 6 m). Would vaccinating older children have a significant public health impact? We developed a mathematical model to explore the benefits of a vaccine against RSV. METHODS AND FINDINGS: We have used a deterministic age structured model capturing the key epidemiological characteristics of RSV and performed a statistical maximum-likelihood fit to age-specific hospitalization data from a developing country setting. To explore the effects of vaccination under different mixing assumptions, we included two versions of contact matrices: one from a social contact diary study, and the second a synthesised construction based on demographic data. Vaccination is assumed to elicit an immune response equivalent to primary infection. Our results show that immunisation of young children (5-10 m) is likely to be a highly effective method of protection of infants (<6 m) against hospitalisation. The majority benefit is derived from indirect protection (herd immunity). A full sensitivity and uncertainty analysis using Latin Hypercube Sampling of the parameter space shows that our results are robust to model structure and model parameters. CONCLUSIONS: This result suggests that vaccinating older infants and children against RSV can have a major public health benefit.
Impact of adolescent age on maternal and neonatal outcomes in the Born in Bradford cohort.

OBJECTIVES: Explore associations between maternal and neonatal outcomes and maternal age, with particular reference to adolescent women. DESIGN: Population-based cohort study. SETTING: Maternity department of a large hospital in Northern England. PARTICIPANTS: Primiparous women delivering a singleton at Bradford Royal Infirmary between March 2007 and December 2010 aged ≤19 years (n=640) or 20-34 years (n=3951). Subgroup analysis was performed using women aged ≤16 years (n=68). Women aged 20-34 years were used as the reference group. PRIMARY OUTCOME MEASURES: Maternal and neonatal outcomes. RESULTS: The odds of extremely low birth weight (<1000 g) were significantly higher in the adolescent group (≤19 years) compared with the reference group (adjusted OR (aOR) 4.13, 95% CI 1.41 to 12.11). The odds of very (<32 weeks) and extremely (<28 weeks) preterm delivery were also higher in the adolescent group (aOR 2.12, 95% CI 1.06 to 4.25 and aOR 5.06, 95% CI 1.23 to 20.78, respectively).Women in the adolescent group had lower odds of gestational diabetes (aOR 0.35, 95% CI 0.20 to 0.62), caesarean delivery (aOR 0.53, 95% CI 0.42 to 0.67 and instrumental delivery (aOR 0.53, 95% CI 0.41 to 0.67). CONCLUSIONS: This study identifies important differences in maternal and neonatal outcomes between women by age group. These findings could help in identifying at-risk groups for additional support and tailored interventions to minimise the risk of adverse outcomes for these vulnerable groups. Further work is needed to identify the causal mechanisms linking age with outcomes in adolescent women where significant gaps in the literature exist.
Dual-color metal-induced and förster resonance energy transfer for cell nanoscopy.

We report a novel method, dual color axial nanometric localization by Metal Induced Energy Transfer (dcMIET), and combine it with Förster Resonant Energy Transfer (FRET) for resolving structural details in cells on the molecular level. We demonstrate the capability of this method on cytoskeletal elements and adhesions in human mesenchymal stem cells (hMSCs). Our approach is based on Fluorescence-Lifetime-Imaging Microscopy (FLIM), and allows for precise determination of the 3D architecture of stress fibers anchoring at focal adhesions, thus yielding crucial information to understand cell-matrix mechanics. In addition to resolving nanometric structural details along the z-axis, we use FRET to gain precise information on the distance between actin and vinculin at focal adhesions.