Miracle-dz/UniFAR-FTUs huggingface dataset:
Recommendations for design and conduct of preclinical in vivo studies of orthopedic device‐related infection

Orthopedic device‐related infection (ODRI), including both fracture‐related infection (FRI) and periprosthetic joint infection (PJI), remain among the most challenging complications in orthopedic and musculoskeletal trauma surgery. ODRI has been convincingly shown to delay healing, worsen functional outcome and incur significant socio‐economic costs. To address this clinical problem, ever more sophisticated technologies targeting the prevention and/or treatment of ODRI are being developed and tested in vitro and in vivo. Among the most commonly described innovations are antimicrobial‐coated orthopedic devices, antimicrobial‐loaded bone cements and void fillers, and dual osteo‐inductive/antimicrobial biomaterials. Unfortunately, translation of these technologies to the clinic has been limited, at least partially due to the challenging and still evolving regulatory environment for antimicrobial drug‐device combination products, and a lack of clarity in the burden of proof required in preclinical studies. Preclinical in vivo testing (i.e. animal studies) represents a critical phase of the multidisciplinary effort to design, produce and reliably test both safety and efficacy of any new antimicrobial device. Nonetheless, current in vivo testing protocols, procedures, models, and assessments are highly disparate, irregularly conducted and reported, and without standardization and validation. The purpose of the present opinion piece is to discuss best practices in preclinical in vivo testing of antimicrobial interventions targeting ODRI. By sharing these experience‐driven views, we aim to aid others in conducting such studies both for fundamental biomedical research, but also for regulatory and clinical evaluation. © 2019 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 37:271–287, 2019.
The characteristics of blood glucose fluctuations in patients with fulminant type 1 diabetes mellitus in the stable stage

ABSTRACT Objective: The aim was to characterize blood glucose fluctuations in patients with fulminant type 1 diabetes (FT1DM) at the stable stage using continuous blood glucose monitoring systems (CGMSs). Subjects and methods: Ten patients with FT1DM and 20 patients with classic type 1 diabetes mellitus (T1DM) (the control group) were monitored using CGMSs for 72 hours. Results: The CGMS data showed that the mean blood glucose (MBG), the standard deviation of the blood glucose (SDBG), the mean amplitude glycemic excursions (MAGE), the blood glucose areas and the percentages of blood glucose levels below 13.9 mmol/L were similar between the two groups. However, the percentage of blood glucose levels below 3.9 mmol/L was significantly higher in the FT1DM group compared to the T1DM group (p < 0.05). The minimum (Min) blood glucose level in the FT1DM group was significantly lower than that of the T1DM group (p < 0.05). Patients with FT1DM had severe dysfunction of the islet beta cells and alpha cells compared to patients with T1DM, as indicated by lower C-peptide values and higher glucagon/C-peptide values. Conclusion: In conclusion, patients with FT1DM at the stable stage were more prone to hypoglycemic episodes as recorded by CGMSs, and they had a greater association with severe dysfunction of both the beta and alpha islet cells compared to patients with T1DM.
Effect of Fecal Microbiota Transplantation on 8-Week Remission in Patients With Ulcerative Colitis: A Randomized Clinical Trial

Importance High-intensity, aerobically prepared fecal microbiota transplantation (FMT) has demonstrated efficacy in treating active ulcerative colitis (UC). FMT protocols involving anaerobic stool processing methods may enhance microbial viability and allow efficacy with a lower treatment intensity. Objective To assess the efficacy of a short duration of FMT therapy to induce remission in UC using anaerobically prepared stool. Design, Setting, and Participants A total of 73 adults with mild to moderately active UC were enrolled in a multicenter, randomized, double-blind clinical trial in 3 Australian tertiary referral centers between June 2013 and June 2016, with 12-month follow-up until June 2017. Interventions Patients were randomized to receive either anaerobically prepared pooled donor FMT (n = 38) or autologous FMT (n = 35) via colonoscopy followed by 2 enemas over 7 days. Open-label therapy was offered to autologous FMT participants at 8 weeks and they were followed up for 12 months. Main Outcomes and Measures The primary outcome was steroid-free remission of UC, defined as a total Mayo score of ⩽2 with an endoscopic Mayo score of 1 or less at week 8. Total Mayo score ranges from 0 to 12 (0 = no disease and 12 = most severe disease). Steroid-free remission of UC was reassessed at 12 months. Secondary clinical outcomes included adverse events. Results Among 73 patients who were randomized (mean age, 39 years; women, 33 [45%]), 69 (95%) completed the trial. The primary outcome was achieved in 12 of the 38 participants (32%) receiving pooled donor FMT compared with 3 of the 35 (9%) receiving autologous FMT (difference, 23% [95% CI, 4%-42%]; odds ratio, 5.0 [95% CI, 1.2-20.1]; P = .03). Five of the 12 participants (42%) who achieved the primary end point at week 8 following donor FMT maintained remission at 12 months. There were 3 serious adverse events in the donor FMT group and 2 in the autologous FMT group. Conclusions and Relevance In this preliminary study of adults with mild to moderate UC, 1-week treatment with anaerobically prepared donor FMT compared with autologous FMT resulted in a higher likelihood of remission at 8 weeks. Further research is needed to assess longer-term maintenance of remission and safety. Trial Registration anzctr.org. au Identifier: ACTRN12613000236796
The depth of the implant mucosal tunnel modifies the development and resolution of experimental peri‐implant mucositis: A case–control study

Abstract Background Resolution and prevention of peri‐implant mucositis are a key in preventing peri‐implantitis. This case–control study aims to assess the modifying effect of a deep mucosal tunnel (DMT) on the induction and resolution phases of experimental peri‐implant mucositis. Methods Nineteen subjects with a tissue level implant were assigned to cases (DMT, depth ≥3 mm) or controls (shallow mucosal tunnel ≤1 mm, SMT). Subjects underwent a standard experimental peri‐implant mucositis protocol characterized by an oral hygiene optimization phase, a 3‐week induction phase using an acrylic stent to prevent self‐performed oral hygiene at the experimental implant, and a 3 + 2 weeks resolution phase. Modified plaque (mPI), gingival index (mGI) and peri‐implant sulcus fluid IL‐1β concentrations were measured over time. Differences between DMT and SMT were assessed with the Mann–Whitney test. Results Modified plaque index and mGI increased in parallel during the induction phase. After resumption of oral hygiene practice, mPI and mGI resolved towards baseline values in the SMT group. In DMT, mPI and mGI values diverged: plaque resolved but resolution of inflammation was delayed and of smaller magnitude during the first 3 weeks after resumption of oral hygiene. IL‐1β concentrations were significantly higher in DMT at 21 days (end of induction) and during the resolution phase corroborating the clinical findings. Removal of the crown and submucosal professional cleaning were needed to revert mGI to baseline values in DMT implants. Conclusions The depth of the mucosal tunnel modifies the resolution of experimental peri‐implant mucositis at transmucosal implants. This observation raises important questions on the effectiveness of self‐performed oral hygiene in cases where implants are placed deeper and the ability to resolve mucositis and effectively prevent peri‐implantitis in such situations.
Maturation changes the excitability and effective connectivity of the frontal lobe: A developmental TMS–EEG study

The combination of transcranial magnetic stimulation with simultaneous electroencephalography (TMS–EEG) offers direct neurophysiological insight into excitability and connectivity within neural circuits. However, there have been few developmental TMS–EEG studies to date, and they all have focused on primary motor cortex stimulation. In the present study, we used navigated high‐density TMS–EEG to investigate the maturation of the superior frontal cortex (dorsal premotor cortex [PMd]), which is involved in a broad range of motor and cognitive functions known to develop with age. We demonstrated that reactivity to frontal cortex TMS decreases with development. We also showed that although frontal cortex TMS elicits an equally complex TEP waveform in all age groups, the statistically significant between‐group differences in the topography of the TMS‐evoked peaks and differences in current density maps suggest changes in effective connectivity of the right PMd with maturation. More generally, our results indicate that direct study of the brain's excitability and effective connectivity via TMS–EEG co‐registration can also be applied to pediatric populations outside the primary motor cortex, and may provide useful information for developmental studies and studies on developmental neuropsychiatric disorders.
The influence of working memory performance on event-related potentials in young and older adults

ABSTRACT Variations in brain activation may lead to individual differences in working memory (WM) performance. Such differences may account for contradictory findings in the literature relating to age-related changes in neural activation during WM tasks. In the present study, 39 young adults (aged 18–30) and 34 older adults (aged 65+) completed an n-back task while their electroencephalography, accuracy, and reaction time was recorded. They were then categorized as high or low performers. High performers had larger P3b and parietal P200 amplitudes and smaller parietal N200 amplitudes than low performers. High-performing older adults exhibited larger parietal P200 amplitudes than low-performing older adults, and similar P3bs to young adults during the 2-back. Low-performing older adults, in contrast, exhibited smaller parietal P3bs than young adults during the 2-back. These findings suggest that brain activity during a WM task is influenced by individual differences in performance level. Moreover, some older adults can maintain high WM performance and capacity through recruitment of additional brain regions.
Immunogenicity assay development and validation for biological therapy as exemplified by ustekinumab

Introduction of biotherapeutics has been a major milestone in the treatment of different chronic diseases. Nevertheless, the immune system can recognize the administered biological as non‐self and respond with generation of anti‐drug antibodies (ADA), including neutralizing ADA (nADA). Immunogenic responses may result in altered drug dynamics and kinetics leading to changes in safety and efficacy. However, there are several challenges with standard techniques for immunogenicity testing. Ustekinumab (UST), used in different inflammatory diseases, is a therapeutic antibody directed against the shared p40 subunit of interleukin (IL)‐12 and IL‐23, interfering in the pathogenically crucial T helper type 1 (Th1)/Th17 pathway. We established and validated different approaches for detection and quantitation of UST, UST‐specific ADA and nADA. Addressing the obstacle of complex formation of UST with nADA, we developed an acidification assay to approach the total amount of nADA. Validated methods were based on surface plasmon resonance spectroscopy (SPR), enzyme‐linked immunosorbent assay (ELISA) and a cell‐based approach to characterize neutralizing capacity of nADA. Parameters assessed were determination and quantitation limits, linearity, range, precision, accuracy and selectivity. Quantitation of ADA and UST was feasible at lower concentrations using ELISA, whereas SPR showed a wider linear range for determination of ADA and UST. Accuracy, precision and linearity for quantitation were comparable using ELISA, SPR and the cell‐based approach. All validated parameters fulfill the requirements of regulatory agencies. A combination of the testing approaches could address the increasing demand of precision medicine as it can be suitable for capturing the whole spectrum of immunogenicity and is transferable to other biologicals.
Arterial thromboembolic events preceding the diagnosis of cancer in older persons.

Cancer patients face an increased risk of arterial thromboembolism; however, it is uncertain when this excess risk begins. This study evaluated the risk of arterial thromboembolism before cancer diagnosis. Using the population-based Surveillance Epidemiology and End Results-Medicare linked dataset, we identified 374 331 patients ≥67 years of age with a new primary diagnosis of breast, lung, prostate, colorectal, bladder, uterine, pancreatic, gastric cancer, or non-Hodgkin lymphoma from 2005 through 2013. Cancer patients were individually matched by demographics and comorbidities to Medicare beneficiaries without cancer, who served as controls. Validated diagnosis codes were used to identify arterial thromboembolic events, defined as a composite of myocardial infarction or ischemic stroke. The Mantel-Haenszel estimator was used to compare risks of arterial thromboembolic events between cancer and noncancer groups during 30-day periods in the 360 days before date of cancer diagnosis. From 360 to 151 days before cancer diagnosis, the 30-day interval risks of arterial thromboembolic events were similar between cancer patients and matched controls. From 150 to 1 day before cancer diagnosis, the interval 30-day risks of arterial thromboembolic events were higher in cancer patients vs matched controls, progressively increasing as the cancer diagnosis date approached and peaking during the 30 days immediately before cancer diagnosis, when 2313 (0.62%) cancer patients were diagnosed with an arterial thromboembolic event vs 413 (0.11%) controls (odds ratio, 5.63; 95% confidence interval, 5.07-6.25). In conclusion, the risk of arterial thromboembolic events begins to increase 150 days before the date of cancer diagnosis in older persons and peaks in the 30 days before.
Evaluation of adding the CANTAB computerized neuropsychological assessment battery to a traditional battery in a tertiary care center for veterans

Abstract Numerous advantages of and concerns about computerized neuropsychological assessment systems have been noted. Here we report a program evaluation of incorporating a computerized system, the Cambridge Neuropsychological Test Automated Battery (CANTAB), in our tertiary assessment center for Veterans. Patients were 23 consecutive referrals to the Western War Related Illness and Injury Study Center, an interdisciplinary assessment center within the Veterans Affairs Healthcare System for Veterans with complex medical presentations. Patients were administered both the CANTAB and a brief traditional neuropsychological battery. The correlation between global composite scores from each method was . 71 (p < .05), indicating “good” concordance. Concordance was “fair” to “good” for scores on specific cognitive domains. However, concordance was lower when classifying patients’ cognition as “impaired” or “not-impaired” based on a cutoff score. Despite the CANTAB’s primarily visuospatial interface, discrepancy between the two methods’ scores was not associated with patients’ visuospatial abilities. The two methods were similarly sensitive to deficits associated with posttraumatic stress disorder, which is prevalent among the Center’s patients. The CANTAB was judged to be a valid and useful complement to, but not an acceptable alternative to a traditional neuropsychologist-administered cognitive assessment battery for the Center’s specific patients and needs.
Rapid and reproducible phosphopeptide enrichment by tandem metal oxide affinity chromatography: application to boron deficiency induced phosphoproteomics

Mass spectrometry has been instrumental in enabling the study of molecular signaling on a cellular scale by way of site-specific quantification of protein post-translational modifications, in particular phosphorylation. Here we describe an updated tandem metal oxide affinity chromatography (MOAC) combined phosphoprotein/phosphopeptide enrichment strategy, a scalable phosphoproteomics approach that allows rapid identification of thousands of phosphopeptides in plant materials. We implemented modifications to several steps of the original tandem MOAC procedure to increase the amount of quantified phosphopeptides and hence site-specific phosphorylation of proteins in a sample beginning with the less amounts of tissue and a substantially smaller amount of extracted protein. We applied this technology to generate time-resolved maps of boron signaling in Arabidopsis roots. We show that the successive enrichment of phosphoproteins in a first and phosphopeptide extraction in a second step using our optimized procedure strongly enriched the root phosphoproteome. Our results reveal that boron deficiency affects over 20% of the measured root phosphoproteome and that many phosphorylation sites with known biological function, and an even larger number of previously undescribed sites, are modified during the time course of boron deficiency. We identify transcription factors as key regulators of hormone signaling pathways that modulate gene expression in boron deprived plants. Furthermore, our phosphorylation kinetics data demonstrate that mitogen-activated protein kinase (MAPK) cascades mediate polarized transport of boron in Arabidopsis roots. Taken together, we establish and validate a robust approach for proteome-wide phosphorylation analysis in plant biology research.
Rethomics: An R framework to analyse high-throughput behavioural data

The recent development of automatised methods to score various behaviours on a large number of animals provides biologists with an unprecedented set of tools to decipher these complex phenotypes. Analysing such data comes with several challenges that are largely shared across acquisition platform and paradigms. Here, we present rethomics, a set of R packages that unifies the analysis of behavioural datasets in an efficient and flexible manner. rethomics offers a computational solution to storing, manipulating and visualising large amounts of behavioural data. We propose it as a tool to bridge the gap between behavioural biology and data sciences, thus connecting computational and behavioural scientists. rethomics comes with a extensive documentation as well as a set of both practical and theoretical tutorials (available at https://rethomics.github.io).
HIV-positive men involvement in pregnancy care and infant feeding of HIV-positive mothers in rural Maputo Province, Mozambique

Introduction: Male involvement has been considered crucial to prevent passing HIV from mother to infant in sub-Saharan Africa. However, little is known about how HIV-positive Mozambican men and their female partners perceive and involve themselves in pregnancy and breastfeeding. This study analyses HIV-positive men’s role on compliance of medical advice recommended to prevent passing HIV from mother to infant. Material and method: A qualitative study was carried out consisting of in-depth interviews with HIV-positive men and women, focus group discussions, plus semi-structured interviews with nurses and community health workers. Results: HIV-positive men provided food and money for transport for their wives during pregnancy and breastfeeding. Some men encouraged their wives to attend antenatal care visits. However, most men did not accompany their wives to antenatal care, childbirth or postnatal visits due to work obligations and perceived stigmatisation in the community. Also, most men perceived a maternal clinic as a place for women. HIV-positive men supported adherence to antiretroviral therapy for their wives and infants, and they complied with prescriptions regarding antiretroviral therapy for themselves. Nonetheless, they did not often allow their wives to use contraception. Conclusion: Some HIV-positive men supported women to follow some medical advice to prevent transmitting HIV from mother to infant.
Career aspirations and reasons for choosing dentistry as a career – A survey of dental students in gandhi dental college and hospital, Bhubaneswar.

The motivations for choosing a career are yet not clearly defined. The purpose of this study was to investigate why students at Gandhi Dental College had chosen dentistry as their career, to consider the factors that had influenced their decision and to study their different career goals. Career aspiration of Dental students was assessed with the help of a questionnaire which was distributed among dental students and interns. Answers were then analyzed to find differences between the groups. The overall response rate was 86%. Main reason to enter this profession was their own interest (53.91%). 57.39% of the undergraduates and interns aspired to do post-graduation for better salaries and good job opportunities. 62.17% wanted to go abroad for further studies commonly to the USA and wished for some career counseling in this regard. When asked whether they would advice their friends to take up dentistry 81.74% said yes mainly because of good scope while 18.26% said no due to factors like increased stress and saturation in this field.
Effects of fresh-cow diseases on reproduction in a large commercial dairy herd

The 2007 NAHMS (National Animal Health Monitoring System) survey indicated that early lactation health issues are major factors influencing reproduction and culling on U.S. dairy herds. The objective of this study was to evaluate fresh-cow health during the first 30 days in milk, and its association with days to pregnancy in the concurrent lactation. Data were collected on cattle that calved over a two month period (July and August 2009) on a dairy farm located in the Upper Midwest region of the U.S. Health and production data were collected daily for each cow from the beginning of lactation until the majority of the study population was confirmed pregnant. Both a competing risk analysis and a semi-parametric Cox regression model were used to test the association between specific health-related events and days to pregnancy and the outcomes of the two models were compared. These analyses showed metritis and dystocia in the first 30 days of lactation were associated with greater days to pregnancy. The only difference noted between parities was that lactation-five and greater cows were significantly associated with greater days to pregnancy. The two analyses showed conflicting significance of association between retained placenta, ketosis, twinning, lameness, and other non-specific illnesses with days to pregnancy. This study found that a competing risk analysis and a semi-parametric regression model were appropriate methods to analyze time sensitive data such as reproductive efficiency. This study supports the evidence that parity, metritis, retained placenta, ketosis, dystocia, twinning, lameness, and other non-specific illnesses can have an impact on reproductive efficiency.