Miracle-dz/UniFAR-FTUs huggingface dataset:
Considerations for Dose Selection and Clinical Pharmacokinetics/Pharmacodynamics for the Development of Antibacterial Agents

In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. ABSTRACT In June 2017, The National Institute of Allergy and Infectious Diseases, part of the National Institutes of Health, organized a workshop entitled “Pharmacokinetics-Pharmacodynamics (PK/PD) for Development of Therapeutics against Bacterial Pathogens” to discuss details and critical parameters of various PK/PD methods and identify approaches for linking human pharmacokinetic (PK) data and drug efficacy analyses. The workshop participants included individuals from academia, industry, and government. This and the accompanying minireview on nonclinical PK/PD summarize the workshop discussions and recommendations. It is important to consider how information like PK/PD can support the clinical effectiveness of new antibacterial drugs, as PK/PD data have become central to antibacterial drug development programs. Key clinical considerations for antibacterial dose selection and clinical PK/PD characterization discussed in this minireview include a robust assessment of PK in the patient population of interest, critical considerations for assessing drug penetration in the lung for the treatment of pneumonia, and an emphasis on special populations, including patients with renal impairment and augmented renal function, as well as on dosing in obese and pediatric patients. Successful application of such approaches is now used to provide a more informative drug development package to support the approval of new antibiotics.
Area-Level Walkability and the Geographic Distribution of High Body Mass in Sydney, Australia: A Spatial Analysis Using the 45 and Up Study

Improving the walkability of built environments to promote healthy lifestyles and reduce high body mass is increasingly considered in regional development plans. Walkability indexes have the potential to inform, benchmark and monitor these plans if they are associated with variation in body mass outcomes at spatial scales used for health and urban planning. We assessed relationships between area-level walkability and prevalence and geographic variation in overweight and obesity using an Australian population-based cohort comprising 92,157 Sydney respondents to the 45 and Up Study baseline survey between January 2006 and April 2009. Individual-level data on overweight and obesity were aggregated to 2006 Australian postal areas and analysed as a function of area-level Sydney Walkability Index quartiles using conditional auto regression spatial models adjusted for demographic, social, economic, health and socioeconomic factors. Both overweight and obesity were highly clustered with higher-than-expected prevalence concentrated in the urban sprawl region of western Sydney, and lower-than-expected prevalence in central and eastern Sydney. In fully adjusted spatial models, prevalence of overweight and obesity was 6% and 11% lower in medium-high versus low, and 10% and 15% lower in high versus low walkability postcodes, respectively. Postal area walkability explained approximately 20% and 9% of the excess spatial variation in overweight and obesity that remained after accounting for other individual- and area-level factors. These findings provide support for the potential of area-level walkability indexes to inform, benchmark and monitor regional plans aimed at targeted approaches to reducing population-levels of high body mass through environmental interventions. Future research should consider potential confounding due to neighbourhood self-selection on area-level walkability relations.
A person-centered approach to study intimacy and sexuality in residential care facility (RCF) clients with dementia: Methodological considerations and a guide to study design.

BACKGROUND The person-centered perspective of residential care facility (RCF) residents with dementia with regard to their intimate and sexual lives is largely neglected in research. OBJECTIVE We aim to provide methodological considerations and reflections on a performed qualitative study. Recommendations and a guide to study design are provided to inform and encourage future research on the inclusion of people with dementia as participants. METHODS Methodological recommendations and reflections are described in chronological order of the procedure. Fragments of interviews are included for further illustration and clarification. RESULTS Considering preparation, close involvement of clinical practice, and extensive deliberation regarding study design tended to be important. Considering procedure, investment in contacts with clinical practice and authorized representatives; an introduction meeting; person-centered inclusion and consent; profound skills in interviewing participants with dementia; and flexibility in data collection were proven of importance. Considering data analysis and study quality, including field notes and aiming at a balance between study quality and practicability to enhance study 'rigor' were found important. CONCLUSION Including the person-centered perspective in research on intimacy and sexuality of RCF residents with dementia, is challenging and takes a flexible and creative approach. It is, however, worthwhile to close the gap in literature.
Design and Implementation of a Secure Computing Environment for Analysis of Sensitive Data at an Academic Medical Center

Academic medical centers need to make sensitive data from electronic health records, payer claims, genomic pipelines, and other sources available for analytical and educational purposes while ensuring privacy and security. Although many studies have described warehouses for collecting biomedical data, few studies have described secure computing environments for analysis of sensitive data. This case report describes the Weill Cornell Medicine Data Core with respect to user access, data controls, hardware, software, audit, and financial considerations. In the 2.5 years since launch, the Data Core has supported more than 200 faculty, staff, and students across nearly 60 research and education projects. Other institutions may benefit from adopting elements of the approach, including tools available on Github, for balancing access with privacy and security.
ACAT: A Fast and Powerful P-value Combination Method for Rare-variant Analysis in Sequencing Studies

Set-based analysis that jointly tests the association of variants in a group has emerged as a popular tool for analyzing rare and low-frequency variants in sequencing studies. The existing set-based tests can suffer significant power loss when only a small proportion of variants are causal, and their powers can be sensitive to the number, effect sizes and effect directions of the causal variants and the choices of weights. Here we propose an Aggregated Cauchy Association Test (ACAT), a general, powerful and computationally efficient p-value combination method to boost power in sequencing studies. First, by combining variant-level p-values, we use ACAT to construct a set-based test (ACAT-V) that is particularly powerful in the presence of only a small number of casual variants in a variant set. Second, by combining different variant set-level p-values, we use ACAT to construct an omnibus test (ACAT-O) that combines the strength of multiple complimentary set-based tests including the burden test, Sequence Kernel Association Test (SKAT) and ACAT-V. Through analysis of extensively simulated data and the whole-genome sequencing data from the Atherosclerosis Risk in Communities (ARIC) study, we demonstrate that ACAT-V complements the SKAT and burden test, and that ACAT-O has a substantially more robust and higher power than the alternative tests.
Cationic Porphyrin-Graphene Oxide Hybrid: Donor-Acceptor Composite for Efficient Photoinduced Electron Transfer.

Non-covalent nanohybrids composed of cationic 5,10,15,20-tetra(4-trimethylammoniophenyl)porphyrin tetra(p-toluenesulfonate) (TMAP) and the graphene oxide sheets were prepared under two pH values (6.2 vs. 1.8). The TMAP molecule was positively charged, regardless of the pH value during preparation. However, protonation of the imino nitrogens increased the overall charge of the porphyrin molecule from +4 to +6 (TMAP4+ and TMAP6+ ). It was found that at acidic pH, interaction of TMAP6+ with GO was largely suppressed. On the other hand, results of FTIR, Raman spectroscopy, thermogravimetric analysis, atomic force microscopy (AFM) and elemental analysis confirmed effective non-covalent functionalization of graphene oxide with cationic porphyrin at pH 6.2. The TMAP4+ -GO hybrids exhibited well defined structure with a monolayer of TMAP4+ on the GO sheets as confirmed by AFM. Formation of the ground-state TMAP4+ -GO complex in solution was monitored by the red-shift of the porphyrin Soret absorption band. This ground-state interaction between TMAP4+ and GO is responsible for the static quenching of the porphyrin emission. Fluorescence was not detected for the nanohybrid which indicated that a very fast deactivation process had to take place. Ultrafast time-resolved transient absorption spectroscopy clearly demonstrated the occurrence of electron transfer from the photoexcited TMAP4+ singlet state to GO sheets, as proven by the formation of a porphyrin radical cation.
Outbreak of Brown Spot of Tobacco Caused by Alternaria alternata in Connecticut and Massachusetts.

In early August 2000, a leaf spot disease of broadleaf tobacco (Nicotiana tabacum L.) was widespread and severe in Connecticut and Massachusetts. The spots were roughly circular, with necrotic centers and concentric rings and often surrounded by a yellow halo. Spots ranged in size from small fleck symptoms (approximately 1 mm) to large lesions 1 to 3 cm in diameter. The putative tobacco brown spot pathogen, Alternaria alternata (Fr.:Fr.) Keissl. , was isolated on potato-dextrose agar from symptomatic tissues after surface-sterilization for 30 s in 0.525% NaOCl. Brown conidia were produced in culture, often in chains. Conidia were variable in size, but tapered to a lighter colored short beak that was usually less than one quarter the length of the conidia (1). Healthy, detached broadleaf leaves (the first fully expanded leaves) were inoculated with 25 drops (45:1 each) of water alone or water containing 5.0 × 104 conidia combined from ten cultures (four leaves for each treatment). Drops were placed in the area between veins and allowed to air-dry for 3 h. Leaves were then misted and placed in a plastic bag in a growth chamber maintained at 24°C with 8 h light per day. Brown spot symptoms developed in 25% of the inoculated spots but not in areas of water controls after 11 days. Symptomatic tissue was surface-sterilized and A. alternata was consistently reisolated on potato-dextrose agar. Brown spot commonly occurs in the Connecticut River Valley on senescent leaves near the soil; however, in August 2000, symptoms were present on leaves of all ages. The greatly increased incidence and severity of brown spot were likely due to unusually wet conditions during the 2000 cropping season (2). In Windsor, CT, an average of 3 days per week of rain was recorded throughout the growing season. Brown spot symptoms render broadleaf tobacco leaves unsuitable for use as a natural leaf cigar wrapper and result in a complete loss of value. Data released by the New England National Agricultural Statistics Service on 1 September 2000 indicated that broadleaf tobacco losses in Connecticut and Massachusetts were at least 75 and 89% of the total acreage, respectively. References: (1) G. B. Lucas. Tob. Sci. 15:37,1971. (2) J. R. Stavely and C. E. Main. Phytopathology 60:1591, 1970.
ATR Inhibition Potentiates the Radiation-induced Inflammatory Tumor Microenvironment

Purpose: ATR inhibitors (ATRi) are in early phase clinical trials and have been shown to sensitize to chemotherapy and radiotherapy preclinically. Limited data have been published about the effect of these drugs on the tumor microenvironment. Experimental Design: We used an immunocompetent mouse model of HPV-driven malignancies to investigate the ATR inhibitor AZD6738 in combination with fractionated radiation (RT). Gene expression analysis and flow cytometry were performed posttherapy. Results: Significant radiosensitization to RT by ATRi was observed alongside a marked increase in immune cell infiltration. We identified increased numbers of CD3+ and NK cells, but most of this infiltrate was composed of myeloid cells. ATRi plus radiation produced a gene expression signature matching a type I/II IFN response, with upregulation of genes playing a role in nucleic acid sensing. Increased MHC I levels were observed on tumor cells, with transcript-level data indicating increased antigen processing and presentation within the tumor. Significant modulation of cytokine gene expression (particularly CCL2, CCL5, and CXCL10) was found in vivo, with in vitro data indicating CCL3, CCL5, and CXCL10 are produced from tumor cells after ATRi + RT. Conclusions: We show that DNA damage by ATRi and RT leads to an IFN response through activation of nucleic acid–sensing pathways. This triggers increased antigen presentation and innate immune cell infiltration. Further understanding of the effect of this combination on the immune response may allow modulation of these effects to maximize tumor control through antitumor immunity.
Adaptive and Maladptive Effects of SMAD3 Signaling in the Adult Heart After Hemodynamic Pressure Overloading

Background—Previous studies suggest that transforming growth factor-&bgr; provokes cardiac hypertrophy and myocardial fibrosis; however, it is unclear whether the deleterious effects of transforming growth factor-&bgr; signaling are conveyed through SMAD-dependent or SMAD-independent signaling pathways. Methods and Results—To determine the contribution of SMAD-dependent signaling to cardiac remodeling, we performed transaortic constriction in SMAD3 null (SMAD3−/−) and littermate control mice (age, 10 to 12 weeks). Cumulative survival 20 days after transaortic constriction was significantly less in the SMAD3−/− mice when compared with littermate controls (43.6% versus 90.9%, P<0.01). Transaortic constriction resulted in a significant increase in cardiac hypertrophy in the SMAD3−/− mice, denoted by an increase in the heart weight to tibial length ratio and increased myocyte cross-sectional area. Loss of SMAD3 signaling also resulted in a significant 60% decrease in myocardial fibrosis (P<0.05). A microRNA microarray showed that 55 microRNAs were differentially expressed in littermate and SMAD3−/− mice and that 10 of these microRNAs were predicted to bind to genes that regulate the extracellular matrix. Of these 10 candidate microRNAs, both miR-25 and miR-29a were sufficient to decrease collagen gene expression when transfected into isolated cardiac fibroblasts in vitro. Conclusions—The results suggest that SMAD3 signaling plays dual roles in the heart: one beneficial role by delimiting hypertrophic growth and the other deleterious by modulating myocardial fibrosis, possibly through a pathway that entails accumulation of microRNAs that decrease collagen gene expression.
Extraction of curcuminoids from Curcuma longa: comparative study between batch extraction and novel three phase partitioning

Abstract Curcuminoids, the active components of dried rhizome of Curcuma longa have been extracted using batch extraction and three-phase partitioning (TPP) process. The effect of different processing parameters, namely different solvents, extraction time, ammonium sulfate concentration, slurry to tert-butanol ratio, and solute to aqueous ratio on extraction efficiency of TPP, was studied to attain maximum extraction yield. The highest yield of 58.38 mg/g was achieved at 40±2 °C in 150 min, with saturated ammonium sulfate 30% (w/v), slurry to tert-butanol ratio 1:1 (v/v), and turmeric powder to water ratio 1:40 (w/v) in TPP. However, batch extraction using ethanol as a solvent yielded 52.77 mg/g in 180 min extraction time at 40±2 °C with 1:40 (w/v) turmeric powder to water ratio and 400 rpm agitation speed. In view of reference method, i.e., Soxhlet extraction (100%), TPP showed 65.63% yield in 150 min and batch exhibited 59.92% in 180 min. The turmeric extracts obtained by different methods exhibited excellent antioxidant and anti-inflammatory activities equivalent to their respective reference standards. Hence, TPP extraction process assures a rapid and improved recovery of curcuminoids with excellent therapeutic properties. Graphical Abstract Curcuminoids, the active components of dried rhizome of Curcuma longa has been extracted using batch extraction and three-phase partitioning (TPP) process. Research highlights Batch and three phase partitioning (TPP) methods were successfully studied and compared for curcuminoids extraction. Influence of different processing parameters on TPP and batch were optimized. Three phase partition gives more yield than the batch extraction process. The extracts obtained showed excellent antioxidant and anti-inflammatory properties. TPP was found to be rapid method of extraction compared to batch process.
Predictors of unmet needs for communication and mobility assistive devices among youth with a disability: the role of socio-cultural factors

Purpose. Despite the importance of ensuring access to assistive technology, high rates of underutilization remain. Relatively little is known about the characteristics of young people reporting unmet needs for assistive devices, so our study examined this further. Method. Data were analyzed using the 2006 Participation and Activity Limitation Survey. Youth aged 15–24 were selected to explore the characteristics associated with those currently using or reporting unmet needs for communication or mobility devices (n = 15,817). Results. Family structure and language spoken influenced the likelihood of using a communication device for two age subgroups. Meanwhile, language spoken influenced the likelihood of reporting unmet needs for communication assistive devices. The following factors influenced the likelihood of using a mobility device: age, gender, language spoken, income, family structure, and severity of impairment. Gender, geographic location, language spoken, family structure, duration and severity of impairment and presence of other impairments influenced the likelihood of reporting unmet needs for mobility devices. Conclusions. Clinicians need to pay particular attention to the socio-cultural factors of young clients transitioning to adult care.
HIV/AIDS stigma and beliefs about HIV transmission among Israeli Jews and Arabs: an exploratory study

ABSTRACT Although HIV/AIDS incidence in Israel is lower than in most Western countries, HIV/AIDS burden in Israel is on the rise. The Arabs are the largest ethnic minority in Israel. Medical experts in Israel believe that HIV infection rates among Israeli Arabs are underestimated. Moreover, unofficial data suggest that Arabs are significantly less likely than Jews to be tested for HIV and that Arabs are typically diagnosed at a late stage of their disease. Since data concerning the levels of HIV/AIDS stigma and knowledge can inform policy, this exploratory study compares the extent of HIV/AIDS stigma and beliefs about HIV transmission of Jews to those of Arabs. A convenience sample of 183 Israelis was drawn (135 Jews, 48 Arabs). Data were collected via a computerized, open-ended, self-report questionnaire. The main findings revealed that compared to Jews, Arabs reported more misinformation about HIV transmission. Arabs differed from Jews in key manifestations of stigma (support for coercive policies, attribution of blame and responsibility, anger and fear), but not others (avoidance intentions and discomfort). Arabs scored higher on the Summary Index of Stigma, than did Jews. These preliminary findings indicate a need to design culturally-specific interventions to enhance HIV transmission-related knowledge and to debunk stigma among Israeli Arabs.
Global birth prevalence of congenital heart defects 1970–2017: updated systematic review and meta-analysis of 260 studies

Abstract Background Globally, access to healthcare and diagnostic technologies are known to substantially impact the reported birth prevalence of congenital heart disease (CHD). Previous studies have shown marked heterogeneity between different regions, with a suggestion that CHD prevalence is rising globally, but the degree to which this reflects differences due to environmental or genetic risk factors, as opposed to improved detection, is uncertain. We performed an updated systematic review to address these issues. Methods Studies reporting the birth prevalence of CHD between the years 1970–2017 were identified from searches of PubMed, EMBASE, Web of Science and Google Scholar. Data on the prevalence of total CHD and 27 anatomical subtypes of CHD were collected. Data were combined using random-effect models. Subgroup and meta-regression analyses were conducted, focused on geographical regions and levels of national income. Results Two hundred and sixty studies met the inclusion criteria, encompassing 130 758 851 live births. The birth prevalence of CHD from 1970–2017 progressively increased to a maximum in the period 2010–17 of 9.410/1000 [95% CI (confidence interval) 8.602–10.253]. This represented a significant increase over the fifteen prior years (P = 0.031). The change in prevalence of mild CHD lesions (ventricular septal defect, atrial septal defect and patent ductus arteriosus) together explained 93.4% of the increased overall prevalence, consistent with a major role of improved postnatal detection of less severe lesions. In contrast the prevalence of lesions grouped together as left ventricular outflow tract obstruction (which includes hypoplastic left heart syndrome) decreased from 0.689/1000 (95% CI 0.607–0.776) in 1995–99, to 0.475/1000 (95% CI 0.392–0.565; P = 0.004) in 2010–17, which would be consistent with improved prenatal detection and consequent termination of pregnancy when these very severe lesions are discovered. There was marked heterogeneity among geographical regions, with Africa reporting the lowest prevalence [2.315/1000 (95% CI 0.429–5.696)] and Asia the highest [9.342/1000 (95% CI 8.072–10.704)]. Conclusions The reported prevalence of CHD globally continues to increase, with evidence of severe unmet diagnostic need in Africa. The recent prevalence of CHD in Asia for the first time appears higher than in Europe and America, where disease ascertainment is likely to be near-complete, suggesting higher genetic or environmental susceptibility to CHD among Asian people.
Elevated urinary 3‐indoxyl sulfate in sickle cell disease

REFERENCES 1. Hernigou P, Habibi A, Bachir D, Galacteros F. The natural history of asymptomatic osteonecrosis of the femoral head in adults with sickle cell disease. J Bone Joint Surg Am. 2006;88(12):2565-2572. 2. Serjeant GR. The natural history of sickle cell disease. Cold Spring Harb Perspect Med. 2013;3(10):a011783. 3. Steinberg ME, Hayken GD, Steinberg DR. A quantitative system for staging avascular necrosis. J Bone Joint Surg. 1995;77(1):34-41. 4. Milner PF, Kraus AP, Sebes JI, et al. Sickle cell disease as a cause of osteonecrosis of the femoral head. N Engl J Med. 1991;325(21): 1476-1481. 5. Connes P, Alexy T, Detterich J, Romana M, Hardy-Dessources MD, Ballas SK. The role of blood rheology in sickle cell disease. Blood Rev. 2016;30(2):111-118. 6. Neumayr LD, Aguilar C, Earles AN, et al. Physical therapy alone compared with core decompression and physical therapy for femoral head osteonecrosis in sickle cell disease. Results of a multicenter study at a mean of three years after treatment. J Bone Jt Surg Am Vol. 2006;88 (12):2573-2582.