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Background : The definitive treatment of distal vaginal atresia is surgery, but menstrual suppression is often helpful for initial management. Case : A 13-year-old presented with primary amenorrhea and progressive abdominal pain. She was diagnosed with distal vaginal atresia and started on hormonal suppression. She then re-presented with heavy vaginal bleeding and follow-up imaging revealed spontaneous perforation had occurred. There was now evidence of a tract leading from the obstructed vaginal bulge to the introitus. Vaginoplasty was complicated by the tortuosity of the tract. Under ultrasound guidance, a pull-through vaginoplasty was performed. Summary and Conclusion : Spontaneous perforation of an atretic vagina is rare, but in such cases, urgent vaginoplasty is indicated to prevent infection. Despite the presence of a spontaneous tract leading to the obstruction, vaginoplasty can be complex, and intra-operative ultrasound may be beneficial.

Despite the development of efficient anti–human immunodeficiency virus-1 (HIV-1) therapy, HIV-1 associated pathogens remain a major clinical problem. Human cytomegalovirus (CMV) is among the most common HIV-1 copathogens and one of the main causes of persistent immune activation associated with dysregulation of the immune system, cerebrovascular and cardiovascular pathologies, and premature aging. Here, we report on the development of dual-targeted drugs with activity against both HIV-1 and CMV. We synthesized seven compounds that constitute conjugates of molecules that suppress both pathogens. We showed that all seven compounds exhibit low cytotoxicity and efficiently inhibited both viruses in cell lines. Furthermore, we chose a representative compound and demonstrated that it efficiently suppressed replication of HIV-1 and CMV in human lymphoid tissue ex vivo coinfected with both viruses. Further development of such compounds may lead to the development of dual-targeted anti-CMV/HIV-1 drugs.

When infants are identified with a difference of sex development (DSD), a thoughtful approach to imaging is essential to appropriate clinical management. This review provides a comprehensive guide for radiologists who are tasked with performing this critical assignment. We review the embryologic basis of DSDs, with attention to the imaging findings that can indicate specific diagnoses. We also discuss techniques for optimal imaging, including strategies for identifying the gonads by US, tactics for performing genitograms with fluoroscopy and contrast-enhanced US, and the appropriate utilization of MRI. Finally, we review the clinical data and imaging findings that characterize some of the most common DSDs, including congenital adrenal hyperplasia, complete androgen insensitivity syndrome and gonadal dysgenesis.

PURPOSE: Recent preclinical studies suggest combining the HSP90 inhibitor AT13387 (Onalespib) with radiation (IR) against colon cancer and head and neck squamous cell carcinoma (HNSCC). These studies emphasized that AT13387 downregulates HSP90 client proteins involved in oncogenic signaling and DNA repair mechanisms as major drivers of enhanced radiosensitivity. Given the large array of client proteins HSP90 directs, we hypothesized that other key proteins or signaling pathways may be inhibited by AT13387 and contribute to enhanced radiosensitivity. Metabolomic analysis of HSP90 inhibition by AT13387 was conducted to identify metabolic biomarkers of radiosensitization and whether modulations of key proteins were involved in IR-induced tumor vasculogenesis, a process involved in tumor recurrence. METHODS AND MATERIALS: HNSCC and non-small cell lung cancer cell lines were used to evaluate the AT13387 radiosensitization effect in vitro and in vivo. Flow cytometry, immunofluorescence, and immunoblot analysis were used to evaluate cell cycle changes and HSP90 client protein’s role in DNA damage repair. Metabolic analysis was performed using liquid chromatography−Mass spectrometry. Immunohistochemical examination of resected tumors post-AT13387 and IR treatment were conducted to identify biomarkers of IR-induced tumor vasculogenesis. RESULTS: In agreement with recent studies, AT13387 treatment combined with IR resulted in a G2/M cell cycle arrest and inhibited DNA repair. Metabolomic profiling indicated a decrease in key metabolites in glycolysis and tricarboxylic acid cycle by AT13387, a reduction in Adenosine 5’-triphosphate levels, and rate-limiting metabolites in nucleotide metabolism, namely phosphoribosyl diphosphate and aspartate. HNSCC xenografts treated with the combination exhibited increased tumor regrowth delay, decreased tumor infiltration of CD45 and CD11b+ bone marrow−derived cells, and inhibition of HIF-1 and SDF-1 expression, thereby inhibiting IR-induced vasculogenesis. CONCLUSIONS: AT13387 treatment resulted in pharmacologic inhibition of cancer cell metabolism that was linked to DNA damage repair. AT13387 combined with IR inhibited IR-induced vasculogenesis, a process involved in tumor recurrence post-radiotherapy. Combining AT13387 with IR warrants consideration of clinical trial assessment. © 2021 Elsevier Inc. All rights reserved.

Spironolactone reduces morbidity and mortality in patients with heart failure (HF) with reduced ejection fraction (EF) and decreases hospitalizations in HF with preserved EF. To minimize the risk of hyperkalemia, patients must have an estimated glomerular filtration rate (eGFR) > 30 mL/min/1.73 m2 and potassium 40% and 47.9% (n = 58) had an EF ≤ 40% with 69.4% (n = 84) CKD stage 3, 24.8% (n = 30) stage 4, and 5.8% (n = 7) stage 5. Spironolactone was initiated prior to admission (PTA) for 54.5% (n = 66) of patients, while 45.5% (n = 55) of orders were initiated during hospitalization. Eight patients (6.6%) experienced inpatient hyperkalemia—all with PTA spironolactone. Patients who experienced inpatient hyperkalemia had a numerically lower eGFR that was not statistically significant (35.40 vs. 38.22 mL/min/1.73 m2; p = 0.730). Patients with CKD stage 3 (n = 4) had numerically higher rates of inpatient hyperkalemia than stages 4 (n = 1) or 5 (n = 3) (50%, 12.5%, and 37.5% respectively; p

As the field of 3D printing continues to enable the fabrication of biomedical materials and devices, there is increasing demand for the development of biocompatible functional materials with tailor...

Pharmacy has recognized the importance of health disparities and cultural competency (HDCC) education for two decades. More recently, there has been emphasis on incorporating equity, diversity and inclusion (EDI) in pharmacy programs. While many institutions identify a need to incorporate a programmatic approach to HDCC education in order to meet the growing needs of a diverse population, pharmacy curricula continue to lack a holistic, programmatic approach to this vital piece of pharmacy education and the societal challenges our graduates will face throughout their careers. More than ever, pharmacists should graduate with the knowledge, values, and skills to provide culturally appropriate care for a diverse patient population. This commentary is advocating for a holistic, programmatic approach to integrating HDCC education and serves as a call to action for curricular development. It is hoped that this commentary will also set the foundation for additional scholarly work and recommendations regarding a programmatic approach.

Introduction To meet educational standards and provide effective patient care, student pharmacists must be well-prepared to interact with a diverse patient population. Thus, the objective was to assess the effectiveness of four different active learning strategies in enhancing the cultural competency (CC) of student pharmacists at multiple institutions. Methods Across two years, eight colleges/schools of pharmacy integrated two sets of CC activities with different student cohorts (first-third professional year) that were designed to address different aspects of CC. Pre- and post-activity, a modified electronic version of the Clinical Cultural Competency Questionnaire (CCCQ) that included the addition of activity-specific questions was distributed to students. Results A total of 1009 students participated in these activities across eight colleges of pharmacy. The integration of activities resulted in significant increases in most items on three of the four subscales of the CCCQ (knowledge, skills, and encounters/situations). Items on the attitude subscale remained the same. Students also felt the activities were beneficial in addressing their intent. Conclusions Faculty were able to incorporate these activities throughout their respective curricula with minimal time commitment and resources. The activities improved student perceptions of their CC knowledge, skills, and ability to handle encounters and situations. These activities may be useful for other institutions as they determine the best approach to improve student CC and prepare them for practice.

Current guidelines recommend direct-acting oral anticoagulants (DOACs) over warfarin in patients with atrial fibrillation (AF) and valvular heart disease (VHD) without a mechanical valve or moderate to severe mitral stenosis. However, real-world data to support the safety and efficacy of DOACs in this patient population are lacking. Our objective was to assess the safety and effectiveness of DOACs in patients with AF and VHD. This retrospective chart review evaluated patients aged ≥ 18 years with a diagnosis of AF and at least moderate VHD on echocardiogram. Patients were included if they received ≥ 1 month of DOAC therapy from December 2016 to December 2018. Patients were excluded if they received dual antiplatelet therapy or had additional indications for anticoagulation. The primary outcomes were incidence of stroke or systemic embolism (SSE) and major bleeding. In total, 200 patients were included (disease type: aortic, n = 50; mitral, n = 50; tricuspid, n = 50; multivalve, n = 50). Most patients received apixaban (n = 133 [66.5%]) followed by rivaroxaban (n = 50 [25%]) and dabigatran (n = 17 [8.5%]). No patients received edoxaban. The mean CHA2DS2-VASc score was 4.25 and was similar among DOAC cohorts (p = 0.380). The overall SSE rate was 3.5% and was highest for dabigatran (n = 3 [17.6%]) compared with the other DOACs (apixaban, n = 1 [0.8%]; rivaroxaban, n = 3 [6%]; p = 0.001). Rates were similar among different valve types (aortic, n = 3 [6%]; mitral, n = 1 [2%]; tricuspid, n = 2 [4%]; multivalve, n = 1 [2%]; p = 0.653). The overall rate of major bleeding was 5.5% and did not differ among the DOACs (apixaban, n = 5 [3.8%]; rivaroxaban, n = 4 [8%]; dabigatran, n = 2 [11.8%]; p = 0.264) or valve type (aortic, n = 3 [6%]; mitral, n = 2 [4%]; tricuspid, n = 2 [4%]; multivalve, n = 4 [8%]; p = 0.787). In patients with AF and VHD, rates of major bleeding were similar among the DOACs and valve types; however, more patients receiving dabigatran experienced SSE. Further studies are needed to validate these findings.

Background: Sacubitril/valsartan has been incorporated into guidelines based on the results of the PARADIGM-HF trial, which demonstrated reduced mortality in stable patients with heart failure with reduced ejection fraction (HFrEF). Sacubitril/valsartan is recommended in addition to other HF therapies in place of an angiotensin-converting-enzyme inhibitor or angiotensin-receptor-blocker. Objectives: To evaluate the safety and tolerability of sacubitril/valsartan initiation in a community hospital. Design/methods: This single-center, retrospective review evaluated patients that received ≥24 hours of sacubitril/valsartan therapy August 2015-March 2018. The primary outcome included the incidence of hypotensive events during hospitalization. Secondary outcomes included: incidence of inpatient acute kidney injury (AKI) and hyperkalemia, rates of inpatient discontinuation, and change in ejection fraction (EF) ≥30 days after initiation. Results: Of the 59 patients included, 21 (35.6%) experienced a hypotensive event. A total of 6 patients (10.2%) discontinued therapy while inpatient, which was more likely in patients that developed AKI (n = 3; p = 0.005) or those who experienced a hypotensive event (n = 5; p = 0.018). There was a significant difference in mean EF from baseline to ≥ 30 days post-initiation (24.8% vs. 33.2%; p = 0.018). Conclusion: Careful patient selection and monitoring for hypotension, AKI, and hyperkalemia can help increase successful outcomes and improve patient safety.

© 2020 British Journal of AnaesthesiaBackground: Accidental dural puncture is an uncommon complication of epidural analgesia and can cause postdural puncture headache (PDPH). We aimed to describe management practices and outcomes after PDPH treated by epidural blood patch (EBP) or no EBP. Methods: Following ethics committee approval, patients who developed PDPH after accidental dural puncture were recruited from participating countries and divided into two groups, those receiving EBP or no EBP. Data registered included patient and procedure characteristics, headache symptoms and intensity, management practices, and complications. Follow-up was at 3 months. Results: A total of 1001 patients from 24 countries were included, of which 647 (64.6%) received an EBP and 354 (35.4%) did not receive an EBP (no-EBP). Higher initial headache intensity was associated with greater use of EBP, odds ratio 1.29 (95% confidence interval 1.19–1.41) per pain intensity unit increase. Headache intensity declined sharply at 4 h after EBP and 127 (19.3%) patients received a second EBP. On average, no or mild headache (numeric rating score≤3) was observed 7 days after diagnosis. Intracranial bleeding was diagnosed in three patients (0.46%), and backache, headache, and analgesic use were more common at 3 months in the EBP group. Conclusions: Management practices vary between countries, but EBP was more often used in patients with greater initial headache intensity. EBP reduced headache intensity quickly, but about 20% of patients needed a second EBP. After 7 days, most patients had no or mild headache. Backache, headache, and analgesic use were more common at 3 months in patients receiving an EBP.

Mutations in the torsinA-interacting protein 1 (TOR1AIP1) gene result in a severe muscular dystrophy with minimal literature in the pediatric population. We review a case of TOR1AIP1 gene mutation in a 16-year-old Caucasian female with a long history of muscle weakness. Extensive clinical workup was performed and MRI at time of initial presentation demonstrated no significant muscular atrophy with heterogenous STIR hyperintensity of the lower extremity muscles. MRI findings seven years later included extensive atrophy of the lower extremities, with severe progression, including the gluteal muscles, iliopsoas, rectus femoris, and obturator internus. There was also significant atrophy of the rectus abdominis and internal and external oblique muscles, and iliacus muscles. The MRI findings showed more proximal involvement of lower extremities and no atrophy of the tibialis anterior, making TOR1AIP1 the more likely genetic cause. Muscle biopsy findings supported TOR1AIP1 limb-girdle muscular dystrophy. Though rare, TOR1AIP1 gene mutation occurs in pediatric patients and MRI can aid in diagnosis and help differentiate from other types of muscular dystrophy. Genetic and pathology workup is also crucial to accurate diagnosis and possible treatment of these patients.

Background: Guidelines recommend antithrombotic therapy in patients with nonvalvular atrial fibrillation (NVAF) to reduce the risk of stroke and systemic embolism (SSE) based on an assessment utilizing the CHA2DS2-VASc score. However, a treatment gap exists regarding patients at risk for thromboembolic events. Objectives: The aim of this study was to characterize the use of guideline-directed medical therapy (GDMT) to reduce the risk of SSE in patients with NVAF upon hospital discharge. Methods: This retrospective review evaluated patients admitted to a community hospital with NVAF in 2016. All patients were included except for the following: < 18 years of age, concomitant valvular heart disease, expired during hospitalization, or discharged on hospice care. Descriptive statistics were reported for all parameters. Results: A total of 2739 patients with NVAF were included with 59.9% discharged on GDMT to reduce the risk of SSE. A 1% increase in GDMT at discharge was observed in patients admitted with a history of NVAF (n = 2238; 60.1% vs 61.1%). Patients with first-detected NVAF (n = 501) were discharged on GDMT 54.5% of the time. In patients with a high stroke risk, concomitant heart failure ( P = .001) and a lower HAS-BLED score (mean = 2.85 vs 3.18; P < .0001) were associated with receiving GDMT upon discharge. However, patients with increased age (mean = 78.5 vs 76.4; P < .0001), vascular disease ( P = .02), prior major bleeding ( P < .0001), or first-detected NVAF ( P < .0001) were less likely to be discharged on GDMT. Conclusions: Consistent with published registry data, a gap was observed in the use of GDMT to reduce the risk of SSE in patients with NVAF at this institution. Further investigation into methods for improvement is warranted.

This article is devoted to topical issues of cadastral valuation of land in the composition of horticultural and gardening associations of the Novosibirsk region. The main factors affecting the specific indicator of land cadastral value (KSZ) are presented. The results of 2 stages of the cadastral valuation of land for horticulture and horticulture as of January 1, 2008 and January 1, 2013 are considered in detail. To determine the deviation of the average value of the cadastral value of land plots, a comparative analysis of specific KSZ indicators for 23 municipalities of the Novosibirsk region was used. The findings suggest that the cadastral value of land is greatly influenced by the location of gardening and gardening associations, distance from the city, transport infrastructure, soil quality and access roads.

The retroperitoneum is the anatomical space in the abdomen located behind the peritoneum. Structures that lie between the parietal peritoneum and the abdominal wall that are not suspended by a mesentery are classified as retroperitoneal in location and include the pancreas, adrenal glands, kidneys, duodenum, portions of the colon, great vessels, lymph nodes, and lymphatics. In this chapter, normal development and anatomy of the pancreas, adrenal glands, and retroperitoneum are discussed, as well as anatomic variants, congenital abnormalities, inflammatory, traumatic and neoplastic disorders.

Viral infections are one of the important factors that influence the development of mankind. In recent decades, there has been a steady increase in the number of infectious diseases of viral etiology. This is due to the peculiarities of demography and human behavior, uncontrolled urbanization in developing countries, intensification of international travel and trade, lack of effective sanitation, environmental pollution, lack of programs to combat vectors of various diseases, adaptation of viruses themselves to new conditions, the emergence of a large number of refugees, and the shortcomings of public health measures. Such a tense situation is seen as a new challenge not only to modern medicine, but also to humanity as a whole. One of the ways to overcome this problem is the search and development of new highly effective antiviral drugs to combat socially significant diseases. This chapter summarizes the literature data on the study of uracil derivatives, acting as non-nucleoside inhibitors against various RNA and DNA viruses.

In recent years, modern problems of scientometrics have become one of the most actual topics of discussion, both among the scientific community and among government representatives in the field of science and education. The reason is the introduction into scientific reality of a system for assessment the effectiveness of Russian researchers. Accordingly, competent coverage in the information space of the development and application of scientometry requires fundamentally new communication approaches. In this scientific article, the authors analyze methods in promoting scientometric knowledge in the Russian-language information web space and identify the most effective ones.

Widespread latent herpes viral infections within a population can lead to the development of co-infections in HIV-infected patients. These infections are not particularly dangerous for healthy individuals and often occur with minimal symptoms, but for those who are immunocompromised, these infections can accelerate the acute phase of HIV infection and AIDS. Thus, the idea of designing compounds that could combine activity against HIV and co-infections would seem promising. In that regard, eleven compounds were synthesized that represent conjugates of non-nucleoside HIV reverse transcriptase inhibitors and nucleoside inhibitors of the herpes family viruses with the hope that these novel heterodimers will result in dual activity against HIV and concomitant herpes virus infections. ispartof: MOLECULES vol:25 issue:15 ispartof: location:Switzerland status: published

Introduction: Current atrial fibrillation (AF) guidelines recommend flecainide as a first-line rhythm control option in patients without structural heart disease. While there is proven efficacy in clinical trials and guideline support, it is hypothesized that flecainide may be underutilized due to negative outcomes in the CAST trial and that adverse effects are less common than previously perceived. Methods: This retrospective chart review evaluated patients ⩾18 years initiated on flecainide for AF from August 2011 to October 2016 by a cardiology provider at the study site. Exclusion criteria included: Results: Of the 326 patients identified, 144 patients were included. After 6 and 12 months, 102 patients (70.8%) and 89 patients (61.8%) of the 144 were symptomatically controlled. Atenolol use ( p = 0.024), female sex ( p = 0.006), hypertension ( p = 0.040), and dronedarone failure ( p = 0.012) were associated with flecainide discontinuation at 6 months. At 12 months, only previous propafenone failure ( p = 0.032) was significant. Of the 144 patients, 16 (11.1%) reported adverse effects with dizziness, hot flashes, bradycardia, and headache (1.4% each) being the most common. Conclusion: Flecainide is a well-tolerated medication, even at 12 months, with very minor adverse effects. These results support the utility of flecainide in guideline recommended patient populations.

The EVA London Research Workshop is one of the more unique elements of our Conference that we have been keen to develop over many years. Often Postgraduate Students, at Masters or PhD level, or Unaffiliated Artists may feel excluded from prestigious conferences until their research is complete and they can submit a full paper proposal. However apart from their Tutors, Supervisors and Mentors, EVA London provides an almost unique opportunity to submit projects which can be truly described as ‘Work in Progress’. With an audience of International Academics and acknowledged experts in a field, the Research Workshop presentations have often lead to very positive interest and support, and sometimes to future collaborations, or returning to EVA London a year later with a completed piece of Research and a successful Full Conference Proposal. In previous years the presentations have been very popular with our delegates and as Chair of the Research Workshops I can think of a number of occasions where an audience question that began “Have you thought of...” has lead to very exciting new lines of discovery. Sadly in 2020 we will miss that particular interaction, however, we have, as always selected an exciting, ground breaking and quite eclectic group of RW delegates. We hope that by publishing their papers here, either grouped together, around themes, or individually published, you will be keen to contact our RW authors to discuss and develop ideas, as if we had all been able to meet up together in July 2020.

miR-127 is downregulated in breast cancer, where it has been shown to suppress the proliferation, migration, and invasion of breast cancer cells. In triple-negative breast cancer (TNBC), miR-127 downregulation correlates with decreased disease-free and overall patient survival. Tumor suppressor miRNAs may hold therapeutic promise but progress has been limited by several factors, including the lability and high cost of miRNA mimics. Here, we take a novel approach to produce a miR-127 prodrug (miR-127PD), which we demonstrate is processed to mature, functional miR-127-3p in TNBC tumor cells. miR-127PD decreased the viability and motility of TNBC cells, sensitized TNBC cells to chemotherapy, and restricted the TNBC stem cell population. Furthermore, systemic delivery of miR-127PD suppressed tumor growth of MDA-MB-231 and MDA-MB-468 TNBC cells and spontaneous metastasis of MDA-MB-231 cells. In addition, CERK, NANOS1, FOXO6, SOX11, SOX12, FASN, and SUSD2 were identified as novel, functionally important targets of miR-127. In conclusion, our study demonstrates that miR-127 functions as a tumor and metastasis suppressor in TNBC and that delivery of miR-127 may hold promise as a novel therapy. Significance: Exogenous administration of miR-127, which is functionally activated in target cells, inhibits growth and spontaneous metastasis of triple-negative breast cancer.

Learning activities during the Covid-19 pandemic were carried out with an online system even though in reality many institutions had not prepared their systems and infrastructure properly Some e-learning media that are generally used based on survey results include 53 81% google classrooms combined with other applications that are not integrated with the institution’s Learning Management System This condition provides research opportunities to evaluate the effectiveness of online learning, especially how students are motivated to learn the method, where the results can be used as a reference in developing and refining the method Based on many studies, that the gamification model can increase individual motivation in carrying out activities, this study uses a gamification octalysis framework to analyze the extent of the role of gamification in the learning process and measure the amount of student motivation in online learning activities The evaluation results show that the conclusion of the Likert scale results in a “High” level, while the highest score is “Very High” As for the octalysis test scale, the average score of 6 5 on a scale of 1 to 10 The conclusion from the results of this evaluation is that the motivation to learn e-learning during the Covid-19 period is quite high and has the potential to be developed While the results of the Octalysis framework with 8 core drives are still average, for that we need innovation in E-learning which aims to increase student motivation based on Octalysis’s 8 core drives The results of this study recommend that gamification is needed to increase student learning motivation in order to improve learning outcomes © 2020 All Rights Reserved

Advances in device miniaturization, ranging from sensors to transmitters, are driving the need for micro-scaled personalized on-demand power sources. Herein, the tandem operation of a membraneless, two-phase flow microfluidic electrolysis cell and fuel cell (µEC-µFC) is demonstrated, which is a step towards developing an independent micropower source. This device consists of a membraneless double Y-shaped microchannel that encompasses microelectrodes for the microfluidic electrolysis cell (µEC) and microfluidic fuel cell (µFC). A voltage applied to the µEC induces two-phase flow in the µEC-µFC, resulting in the evolution of H2 and O2 gases that are transported to the µFC by convection, and consumed to generate power. The catholyte-anolyte interface of the µEC-µFC behaves as a virtual membrane. The gas product mixing and crossover are averted by controlling the flow rate of electrolyte. Dimensionless numbers are used to characterize the flow in the microchannel. Tandem performance evaluation of µEC-µFC operation in acidic and alkaline electrolytes based on the flow rate (1.4 – 1.6 mL min−1) and µEC operating voltages (2.3 – 2.5 V) is done by polarization and power density curves. The µEC-µFC exhibited 4 h of stable tandem operation. The µEC exhibits 99.98% energy conversion efficiency, with the µFC attaining up to 50% fuel utilization in tandem mode.

Background The majority of undiagnosed diseases manifest with objective findings that warrant further investigation. The Undiagnosed Diseases Network (UDN) receives applications from patients whose symptoms and signs have been intractable to diagnosis; however, many UDN applicants are affected primarily by subjective symptoms such as pain and fatigue. We sought to characterize presenting symptoms, referral sources, and demographic factors of applicants to the UDN to identify factors that may determine application outcome and potentially differentiate between those with undiagnosed diseases (with more objective findings) and those who are less likely to have an undiagnosed disease (more subjective symptoms). Methods We used a systematic retrospective review of 151 consecutive Not Accepted and 50 randomly selected Accepted UDN applications. The primary outcome was whether an applicant was Accepted, or Not Accepted, and, if accepted, whether or not a diagnosis was made. Objective and subjective symptoms and information on prior specialty consultations were collected from provider referral letters. Demographic data and decision data on network acceptance were gathered from the UDN online portal. Results Fewer objective findings and more subjective symptoms were found in the Not Accepted applications. Not Accepted referrals also were from older individuals, reported a shorter period of illness, and were referred to the UDN by their primary care physicians. All of these differences reached statistical significance in comparison with Accepted applications. The frequency of subspecialty consults for diagnostic purposes prior to UDN application was similar in both groups. Conclusions The preponderance of subjective and lack of objective findings in the Not Accepted applications distinguish these from applicants that are accepted for evaluation and diagnostic efforts through the UDN. Not Accepted applicants are referred primarily by their primary care providers after multiple specialist consultations fail to yield answers. Distinguishing between patients with undiagnosed diseases with objective findings and those with primarily subjective findings can delineate patients who would benefit from further diagnostic processes from those who may have functional disorders and need alternative pathways for management of their symptoms. Trial registration clinicaltrials.gov NCT02450851, posted May 21st 2015. Electronic supplementary material The online version of this article (10.1186/s12913-018-3458-2) contains supplementary material, which is available to authorized users.

Our recent trial demonstrated individuals suffering from social anxiety with performance-related concerns who received virtual reality exposure augmented with scopolamine, a cholinergic antagonist, experienced significantly less post-treatment context renewal (CX) than placebo (Craske et al., 2019). The purpose of the present investigation was to determine who specifically benefits from scopolamine by examining hippocampal (HPC) functioning as a moderator of treatment response (Placebo n = 15, SCOP 0.5 mg n = 15, SCOP 0.6 mg n = 15). Skin conductance response to conditional stimulus (SCR-to-CS) termination suggested a dose-response relationship for enhanced HPC functioning individuals, wherein individuals receiving scopolamine demonstrated less fear at CX. In addition, SCR-to-CS onset indicated reduced fear at CX for impaired HPC individuals receiving SCOP 0.5 mg and SCOP 0.6 mg relative to Placebo. Our findings, however, lacked consistency across measures. Scopolamine remains a promising agent and additional research required to further understand its effects.

In a large course, grading assignments is a time-consuming process requiring considerable resources. Online homework software systems are therefore increasingly being utilized. In this article, we will detail our experiences implementing online homework assignments in our course CH E 243: Engineering Thermodynamics; a large, multi-section course with more than 600 students/year in 4 sections. In Year 1 we employed commercial software, and in Year 2 we developed our own online assignments. In both years, assignments had both online and written components. After each year we conducted a survey of the students to gage their perception regarding the implementation and benefits of the online and written assignments, and the contribution of these tools to the students’ ability to master the material. We found that most students were satisfied with the online system, and recommended using it again the following year. Students generally perceived written assignments to be more helpful in achieving mastery of the course material than the online ones. Students perceived our in-house developed system much more positively than the commercial software (as did we). Overall, we perceived that the class performance was better when our own online assignments were used, and the number of students who failed the course was reduced.

With the recent rise of organic electronics, bioelectronics, and transient devices, polymer thin films are finding prominence as substrates, functional layers and diffusion barriers. While some of these applications require degradable polymers, others necessitate materials with high stability and resistance to degradation during operation. Due to their minuscule thickness and mass, it is challenging to characterize the degradation and stability of thin films using existing techniques developed mainly for bulk materials. We introduce here a diffraction-based degradation sensor that can monitor the physical changes that take place as polymer chains are removed during the surface degradation of a polymer film without requiring expensive equipment and extensive sample preparation. To assess the degradation of a polymer film, the surface of the polymer is first patterned with a diffraction grating. This grating forms the key component of the degradation sensor, which also includes a laser and a photodetector to monitor diffraction efficiency as a function of time. When the patterned polymer surface degrades, the diffraction efficiency decreases. As validation, we use this approach to observe both enzymatic degradation of polyhydroxybutyrate films, and dissolution stability of silk. We demonstrate that the degradation sensor can monitor, with high reliability, the degradation of samples with minute mass changes, enabling qualitative and quantitative comparisons in different sample types and/or exposed to various degradation environments.

Although pediatric tumors are largely sporadic in cause, continued advancements in science have elucidated a growing body of tumors that are associated with syndromes. Early identification of these syndromic disorders associated with developing tumors can alter the course of disease and potentially save lives. Medical imaging has a pivotal role in screening surveillance, diagnosis, and management of these tumors. Understanding characteristic manifestations of these syndromes is important to optimize image utilization. This article discusses clinically important syndromes associated with pediatric tumors with brief overview of the background, genetics, and clinical features. Diagnosis, imaging, management, and treatment are also reviewed.

Diagnosis at the edges of our knowledge calls upon clinicians to be data driven, cross-disciplinary, and collaborative in unprecedented ways. Exact disease recognition, an element of the concept of precision in medicine, requires new infrastructure that spans geography, institutional boundaries, and the divide between clinical care and research. The National Institutes of Health (NIH) Common Fund supports the Undiagnosed Diseases Network (UDN) as an exemplar of this model of precise diagnosis. Its goals are to forge a strategy to accelerate the diagnosis of rare or previously unrecognized diseases, to improve recommendations for clinical management, and to advance research, especially into disease mechanisms. The network will achieve these objectives by evaluating patients with undiagnosed diseases, fostering a breadth of expert collaborations, determining best practices for translating the strategy into medical centers nationwide, and sharing findings, data, specimens, and approaches with the scientific and medical communities. Building the UDN has already brought insights to human and medical geneticists. The initial focus has been on data sharing, establishing common protocols for institutional review boards and data sharing, creating protocols for referring and evaluating patients, and providing DNA sequencing, metabolomic analysis, and functional studies in model organisms. By extending this precision diagnostic model nationally, we strive to meld clinical and research objectives, improve patient outcomes, and contribute to medical science.

The paper is a survey to threats modelling in Critical Informational Infrastructure. The main trend analysis, which includes vulnerabilities in processors used in Internet of Things, agile/scrum development, artificial intelligence, is made. As undervaluation of this aspects causes successful penetration of malicious in industrial networks, the relevant threat model is of current concern in the process of building cybersecure system.

The paper describes three corpora of different varieties of BS that are currently being developed with the goal of providing data for the analysis of the diatopic and diachronic variation in non-standard Balkan Slavic. The corpora includes spoken materials from Torlak, Macedonian dialects, as well as the manuscripts of pre-standardized Bulgarian. Apart from the texts, tools for PoS annotation and lemmatization for all varieties are being created, as well as syntactic parsing for Torlak and Bulgarian varieties. The corpora are built using a unified methodology, relying on the pest practices and state-of-the-art methods from the field. The uniform methodology allows the contrastive analysis of the data from different varieties. The corpora under construction can be considered a crucial contribution to the linguistic research on the languages in the Balkans as they provide the lacking data needed for the studies of linguistic variation in the Balkan Slavic, and enable the comparison of the said varieties with other neighbouring languages.

One of the primary goals of genomic medicine, utilizing genomics in clinical care, is to improve diagnosis through identification of genomic conditions to improve clinical management, prevent complications, and promote health. In this paper we explore how genomic medicine is being used to obtain molecular diagnoses for patients with previously undiagnosed diseases in the prenatal, pediatric, and adult clinical settings. We focus on the role of clinical genomic sequencing (exome and genome) in aiding patients with undiagnosed conditions despite extensive clinical evaluation and prior testing. In particular, we explore the impact of combining genomic and phenotypic data and integrating across multiple data types to improve diagnoses for patients with undiagnosed diseases, along with how these genomic sequencing diagnoses change clinical management.

WD40 repeat-containing proteins form a large family of proteins present in all eukaryotes. Here, we identified five pediatric probands with de novo variants in WDR37, which encodes a member of the WD40 repeat protein family. Two probands shared one variant and the others have variants in nearby amino acids outside the WD40 repeats. The probands exhibited shared phenotypes of epilepsy, colobomas, facial dysmorphology reminiscent of CHARGE syndrome, developmental delay and intellectual disability, and cerebellar hypoplasia. The WDR37 protein is highly conserved in vertebrate and invertebrate model organisms and is currently not associated with a human disease. We generated a null allele of the single Drosophila ortholog to gain functional insights and replaced the coding region of the fly gene CG12333/wdr37 with GAL4. These flies are homozygous viable but display severe bang sensitivity, a phenotype associated with seizures in flies. Additionally, the mutant flies fall when climbing the walls of the vials, suggesting a defect in grip strength, and repeat the cycle of climbing and falling. Similar to wall clinging defect, mutant males often lose grip of the female abdomen during copulation. These phenotypes are rescued by using the GAL4 in the CG12333/wdr37 locus to drive the UAS-human reference WDR37 cDNA. The two variants found in three human subjects failed to rescue these phenotypes, suggesting that these alleles severely affect the function of this protein. Taken together, our data suggest that variants in WDR37 underlie a novel syndromic neurological disorder.

In the field of plant disease protection many approaches exist, but all acknowledge the necessity of fast and accurate identification of the source in order to make the most efficient applications. In this work, a remote sensing approach for the detection of Verticillium dahliae in olive fields is presented. A model was created that calculates a spectral index based on Sentinel-2 data and uses it to assess the levels of stress in olive trees in the region of Chalkidiki, Greece. The derived map provides an overview of the situation concerning stress levels in olive fields across a large area and in a small amount of time. Additionally, because of the constant flow of data from the Sentinel satellites, a time series of calculations can be used as an anomaly indicator for regions of interest. This model can be implemented in an e-Infrastructure as a cloud service to further enhance its usability by relevant parties, such as agricultural advisors and scientists.

What is known and objective Gabapentin, a γ-aminobutyric acid derivative, is used for the treatment of partial onset seizures, postherpetic neuralgia, diabetic neuropathy and a host of other neurological disorders. Case description A 44-year-old woman with spinal stenosis was prescribed gabapentin for pain. Two months after initiating therapy, she was diagnosed with a new-onset non-ischaemic cardiomyopathy with an ejection fraction of 36% measured on a transthoracic echocardiogram. What is new and conclusion A patient with suspected gabapentin-induced cardiomyopathy is reported. However, to date, gabapentin therapy has not been associated with risk of the developing a cardiomyopathy.

Exposure therapy is widely empirically supported as a treatment for anxiety disorders, but clinically significant response rates hover around 50%. This study explores strategies for consolidating the exposure memory as a way of improving efficacy. Between-session mental rehearsal of exposure learning was examined as a way of enhancing the effects of exposure therapy. Sixty-two spider-fearful individuals completed baseline questionnaires and a behavioral approach test with a live tarantula, followed by two sessions of in vivo exposures, and a post-assessment one-week later that repeated the baseline questionnaires and behavioral approach test. Skin conductance, subjective distress, and number of steps completed were recorded at each behavioral approach test. Participants were randomized to mental rehearsal or control (non-specific) rehearsal that was prompted on three occasions after each exposure session. Participants in both conditions improved from baseline to post-assessment, but mental rehearsal participants showed significantly greater improvement than control participants across questionnaire measurements of spider fear, subjective distress, and number of steps completed during the behavioral approach test. Findings suggest that between-session mental rehearsal is an effective supplement to exposure therapy. As such, mental rehearsal may be a promising avenue toward increasing treatment response rates across many psychiatric disorders that benefit from exposure therapy.

Purpose Radiation-induced pulmonary fibrosis (RIPF) is a late toxicity of therapeutic radiation. Signaling of the mammalian target of rapamycin drives several processes implicated in RIPF, including inflammatory cytokine production, fibroblast proliferation, and epithelial senescence. We sought to determine if mammalian target of rapamycin inhibition with rapamycin would mitigate RIPF. Methods and Materials C57BL/6NCr mice received a diet formulated with rapamycin (14 mg/kg food) or a control diet 2 days before and continuing for 16 weeks after exposure to 5 daily fractions of 6 Gy of thoracic irradiation. Fibrosis was assessed with Masson trichrome staining and hydroxyproline assay. Cytokine expression was evaluated by quantitative real-time polymerase chain reaction. Senescence was assessed by staining for β-galactosidase activity. Results Administration of rapamycin extended the median survival of irradiated mice compared with the control diet from 116 days to 156 days ( P =.006, log-rank test). Treatment with rapamycin reduced hydroxyproline content compared with the control diet (irradiation plus vehicle, 45.9 ± 11.8 μg per lung; irradiation plus rapamycin, 21.4 ± 6.0 μg per lung; P =.001) and reduced visible fibrotic foci. Rapamycin treatment attenuated interleukin 1β and transforming growth factor β induction in irradiated lungs compared with the control diet. Type II pneumocyte senescence after irradiation was reduced with rapamycin treatment at 16 weeks (3-fold reduction at 16 weeks, P Conclusions Rapamycin protected against RIPF in a murine model. Rapamycin treatment reduced inflammatory cytokine expression, extracellular matrix production, and senescence in type II pneumocytes.

OBJECTIVE. The purpose of this article is to review some of the common indications for pediatric musculoskeletal ultrasound examination, with emphasis given to imaging technique, normal anatomy, and the spectrum of pathologic findings seen in the pediatric population. CONCLUSION. Ultrasound is an essential first-line tool in pediatric musculoskeletal imaging. It aids in determining which patients may benefit from further imaging, including radiography, CT, and MRI.

Nonlethal exposure to ionizing radiation (IR) is a public concern due to its known carcinogenic effects. Although latency periods for IR-induced neoplasms are relatively long, the ability to detect cancer as early as possible is highly advantageous for effective therapeutic intervention. Therefore, we hypothesized that metabolites in the urine from mice exposed to total body radiation (TBI) would predict for the presence of cancer before a palpable mass was detected. In this study, we exposed mice to 0 or 5.4 Gy TBI, collected urine samples periodically over 1 year, and assayed urine metabolites by using mass spectrometry. Longitudinal data analysis within the first year post-TBI revealed that cancers, including hematopoietic, solid, and benign neoplasms, could be distinguished by unique urinary signatures as early as 3 months post-TBI. Furthermore, a distinction among different types of malignancies could be clearly delineated as early as 3 months post-TBI for hematopoietic neoplasms, 6 months for solid neoplasms, and by 1 year for benign neoplasms. Moreover, the feature profile for radiation-exposed mice 6 months post-TBI was found to be similar to nonirradiated control mice at 18 months, suggesting that TBI accelerates aging. These results demonstrate that urine feature profiles following TBI can identify cancers in mice prior to macroscopic detection, with important implications for the early diagnosis and treatment. Cancer Res; 76(6); 1569–77. ©2016 AACR.

In the past decade, with improved surgical technique and knowledge of immunosuppression, pediatric lung and heart transplantation have been established as viable therapeutic interventions for pediatric patients with end-stage cardiopulmonary disease from various underlying congenital and acquired disorders. Although outcomes for pediatric patients are similar to those for adult patients, thoracic organ transplantation in this special age group carries unique challenges for preoperative and postoperative imaging evaluation. The article provides an up-to-date review of the postoperative transplant anatomy, imaging techniques, and complications of pediatric lung and heart transplantation.

Objective. To determine factors predictive of student failure or poor performance on advanced pharmacy practice experiences (APPEs) at a single pharmacy program. Methods. This retrospective cohort evaluated students entering the Doctor of Pharmacy (PharmD) program from 2012-2014 at St. Louis College of Pharmacy. Students who received a grade of F for one or more APPEs (failure group) were compared to all other students (non-failure group). A secondary evaluation compared students with a C or F on one or more APPEs (poor performers) to all other students (non-poor performers). Data were collected on didactic and experiential performance, identifiable professionalism issues from introductory pharmacy practice experiences (IPPEs), and academic honor code violations. Univariable and multivariable logistic regressions were performed to determine factors associated with APPE failure and poor performance. Results. A total of 669 students were analyzed. Twenty-eight students (4.2%) failed one or more APPEs and 81 students (12.1%) were identified as poor performers (grade of C or F). For the primary outcome, professional grade point average (GPA) of less than 2.7, practicum failure, IPPE professionalism issue(s), and pharmacotherapy course failure were identified for inclusion in the multivariable analysis. The IPPE professionalism issue(s) (HR 4.8 [95% CI 1.9-12.4]) and pharmacotherapy course failure (HR 4.2 [95% CI, 1.6-11.1]) were associated with APPE failure on multivariable regression. On the secondary analysis, the same variables were identified for multivariable regression, with professional GPA of less than 2.7 (HR 2.7 [95% CI 1.5-5]), IPPE professionalism issue(s) (HR 3.9 [95% CI 2.2-6.9]), and pharmacotherapy course failure (HR 2.0 [95% CI 1.1-3.7]) associated with poor performance. Conclusion. Poor academic performance and/or identified unprofessional behavior while completing IPPEs are associated with APPE failure and poor performance. Interventions should be aimed at identifying at-risk students and addressing risk factors prior to APPEs.

What is known and objective Current guidelines recommend catheter ablation (CA) for atrial fibrillation (AF) refractory to at least one antiarrhythmic drug (AAD), but do not specify an adequate number of AADs to be trialed prior to considering ablation. The objective of this study was to evaluate the effect of CA success based on the number of AADs failed in patients with paroxysmal or persistent AF. Methods This retrospective cohort study evaluated patients with paroxysmal or persistent AF who underwent an initial CA at a community hospital. Patients with unknown AAD histories, those who did not achieve acute procedural success, or who were lost to follow-up or death unrelated to thromboembolic stroke within 6 months post-ablation were excluded. Catheter ablation success was defined as freedom from AF. The primary outcome was the incidence of AF or atrial flutter captured on an electrocardiogram or other recording device at 3, 6, 9 and 12 months after the procedure. Results and discussion Overall, 99 out of 103 patients completed 1 year of follow-up. Of those patients, 34 of 99 (34.3%) experienced AF recurrence within 1-year post-ablation. There was no significant difference among the categories of number of failed AADs and the recurrence of AF within 12 months post-ablation for zero AADs, 1 AADs and ≥2 AADs (41.7%, 31.3% and 40%, respectively; P = 0.658). What is new and conclusion The results of this study do not support preferentially performing CA on patients who have failed a certain number of AADs. Results are limited by the nature of the study design and a small sample size. Conclusive results would best be addressed by a prospective randomized trial.

BACKGROUND: Many patients remain without a diagnosis despite extensive medical evaluation. The Undiagnosed Diseases Network (UDN) was established to apply a multidisciplinary model in the evaluation of the most challenging cases and to identify the biologic characteristics of newly discovered diseases. The UDN, which is funded by the National Institutes of Health, was formed in 2014 as a network of seven clinical sites, two sequencing cores, and a coordinating center. Later, a central biorepository, a metabolomics core, and a model organisms screening center were added. METHODS: We evaluated patients who were referred to the UDN over a period of 20 months. The patients were required to have an undiagnosed condition despite thorough evaluation by a health care provider. We determined the rate of diagnosis among patients who subsequently had a complete evaluation, and we observed the effect of diagnosis on medical care. RESULTS: A total of 1519 patients (53% female) were referred to the UDN, of whom 601 (40%) were accepted for evaluation. Of the accepted patients, 192 (32%) had previously undergone exome sequencing. Symptoms were neurologic in 40% of the applicants, musculoskeletal in 10%, immunologic in 7%, gastrointestinal in 7%, and rheumatologic in 6%. Of the 382 patients who had a complete evaluation, 132 received a diagnosis, yielding a rate of diagnosis of 35%. A total of 15 diagnoses (11%) were made by clinical review alone, and 98 (74%) were made by exome or genome sequencing. Of the diagnoses, 21% led to recommendations regarding changes in therapy, 37% led to changes in diagnostic testing, and 36% led to variant-specific genetic counseling. We defined 31 new syndromes. CONCLUSIONS: The UDN established a diagnosis in 132 of the 382 patients who had a complete evaluation, yielding a rate of diagnosis of 35%. (Funded by the National Institutes of Health Common Fund.)

xiii Preface xiv Rationale xiv Dissertation organization xiv Authors’ roles xiv Chapter 1. General Introduction 1 Malnutrition 1 The problem of malnutrition 1 Potential solutions to malnutrition 1 Biofortification 3 Iron deficiency and improvements in dietary iron 4 Iron deficiency and absorption 4 Inhibitors and enhancers of iron bioavailability 5 Iron forticants 6 Biofortification of iron 8 Hemoglobin 9 Plant hemoglobin 9 Protein deficiency and seed storage proteins in maize 11 Protein deficiency 11 Dietary requirements for protein 12

Background: Despite well established empiric dose adjustments for drug and disease-state interactions, the impact of body mass index (BM) on warfarin remains unclear. The objective of this study is to evaluate warfarin requirements in hospitalized patients, stratified by BMI. Methods: This retrospective review included two cohorts of patients: cohort A (patients admitted with a therapeutic international normalized ratio (INR)) and cohort B (newly initiated on warfarin during hospitalization). Exclusion criteria included: age under 18 years, pregnancy, INR (goal 2.5–3.5), and warfarin thromboprophylaxis post orthopedic surgery. The primary outcome was mean total weekly dose (TWD) of warfarin based on weight classification: underweight (BMI 2), normal/overweight (BMI 18–29.9 kg/m2), obese (BMI 30–39.9 kg/m2), and morbidly obese (BMI ⩾ 40 kg/m2). Data were extracted from two community hospitals in reverse chronologic order during July 2015–June 2013 until both study institutions evaluated 100 patients per cohort in each BMI classification or until all patients had been evaluated within the prespecified timeframe. Results: A total of 585 patients were included in cohort A (26 underweight, 200 normal/overweight, 200 obese, 159 morbidly obese). There was a statistically significant difference in TWD as determined by one-way analysis of variance ( p < 0.05). A Tukey post hoc test revealed a statistically significantly higher TWD in morbidly obese (41.5 mg) compared with underweight (25.6 mg, p < 0.05), normal/overweight (28.8 mg, p < 0.05) and obese patients (32.4 mg, p < 0.05). In cohort B, 379 patients were evaluated (9 underweight, 166 normal/overweight, 152 obese, 52 morbidly obese). Overall, 191 patients had a therapeutic INR on discharge (88.9% underweight, 52.4% normal/overweight, 44.1% obese, 55.8% morbidly obese, p = 0.035). Of those, there was a statistically significant difference in TWD ( p = 0.021) with a higher TWD in the morbidly obese (41 mg) compared with underweight patients (24.4 mg, p = 0.017). Conclusions: Based on the results of this study, morbidly obese patients may require higher TWD to obtain and maintain a therapeutic INR.

Purpose Sixty-75% of individuals with rare and undiagnosed phenotypes remain undiagnosed after whole exome sequencing (ES). With standard ES reanalysis resolving 10–15% of the ES negatives, further approaches are necessary to maximize diagnoses in these individuals. Methods In 38 ES negative patients an individualized genomic-phenotypic approach was employed utilizing: A) Phenotyping; B) Reanalyses of FASTQ files, with innovative bioinformatics; C) Targeted molecular testing; D) Whole genome sequencing (WGS) and E) Conferring of clinical diagnoses when pathognomonic clinical findings occurred. Results Certain and Highly Likely diagnoses were made in 18/38 (47%) individuals, including identifying two new developmental disorders. The majority of diagnoses (>70%) were due to our bioinformatics, phenotyping and targeted testing identifying variants that were undetected or not prioritized on prior ES. WGS diagnosed 3/18 individuals, with structural variants not amenable to ES. Additionally, Tentative diagnoses were made in three (8%) and in five individuals (13%) candidate genes were identified. Overall, diagnoses/potential leads were identified in 26/38 (68%). Conclusions Our comprehensive approach to ES negatives maximizes the ES and clinical data for both diagnoses and candidate gene identification, without WGS in the majority. This iterative approach is cost-effective and is pertinent to the current conundrum of ES negatives.