A Dense Packing of Regular Tetrahedra

We construct a dense packing of regular tetrahedra, with packing density $D > >.7786157$.Comment: full color versio

In vitro and in vivo studies of the trypanocidal properties of WRR-483 against Trypanosoma cruzi.

BackgroundCruzain, the major cysteine protease of Trypanosoma cruzi, is an essential enzyme for the parasite life cycle and has been validated as a viable target to treat Chagas' disease. As a proof-of-concept, K11777, a potent inhibitor of cruzain, was found to effectively eliminate T. cruzi infection and is currently a clinical candidate for treatment of Chagas' disease.Methodology/principal findingsWRR-483, an analog of K11777, was synthesized and evaluated as an inhibitor of cruzain and against T. cruzi proliferation in cell culture. This compound demonstrates good potency against cruzain with sensitivity to pH conditions and high efficacy in the cell culture assay. Furthermore, WRR-483 also eradicates parasite infection in a mouse model of acute Chagas' disease. To determine the atomic-level details of the inhibitor interacting with cruzain, a 1.5 A crystal structure of the protease in complex with WRR-483 was solved. The structure illustrates that WRR-483 binds covalently to the active site cysteine of the protease in a similar manner as other vinyl sulfone-based inhibitors. Details of the critical interactions within the specificity binding pocket are also reported.ConclusionsWe demonstrate that WRR-483 is an effective cysteine protease inhibitor with trypanocidal activity in cell culture and animal model with comparable efficacy to K11777. Crystallographic evidence confirms that the mode of action is by targeting the active site of cruzain. Taken together, these results suggest that WRR-483 has potential to be developed as a treatment for Chagas' disease

Self-reported illness among Boston-area international travelers: A prospective study

This is the Accepted Manuscript version and was published in final edited form as: Travel Med Infect Dis. 2016 ; 14(6): 604–613. doi:10.1016/j.tmaid.2016.09.009.BACKGROUND: The Boston Area Travel Medicine Network surveyed travelers on travel-related health problems. METHODS: Travelers were recruited 2009-2011 during pre-travel consultation at three clinics. The investigation included pre-travel data, weekly during-travel diaries, and a post-travel questionnaire. We analyzed demographics, trip characteristics, health problems experienced, and assessed the relationship between influenza vaccination, influenza prevention advice, and respiratory symptoms. RESULTS:Of 987 enrolled travelers, 628 (64%) completed all surveys, of which 400 (64%) reported health problems during and/or after travel; median trip duration was 12 days. Diarrhea affected the most people during travel (172) while runny/stuffy nose affected the most people after travel (95). Of those with health problems during travel, 25% stopped or altered plans; 1% were hospitalized. After travel, 21% stopped planned activities, 23% sought physician or other health advice; one traveler was hospitalized. Travelers who received influenza vaccination and influenza prevention advice had lower rates of respiratory symptoms than those that received influenza prevention advice alone (18% vs 28%, P = 0.03). CONCLUSIONS:A large proportion of Boston-area travelers reported health problems despite pre-travel consultation, resulting in inconveniences. The combination of influenza prevention advice and influenza immunization was associated with fewer respiratory symptoms than those who received influenza prevention advice alone

Travelers’ diarrhea and other gastrointestinal symptoms among Boston-area international travelers

INTRODUCTION: Travelers' diarrhea (TD) and non-TD gastrointestinal (GI) symptoms are common among international travelers. In a study of short-term travelers from Switzerland to developing countries, the most common symptom experienced was severe diarrhea (8.5%) followed by vomiting or abdominal cramps (4%).1 GI illnesses were the most frequently reported diagnoses (34%) among ill-returned travelers to GeoSentinel clinics.2 Of those returning to U.S. GeoSentinel clinics, acute diarrhea (30%) was the most common diagnosis.3 In one cohort of U.S. travelers, 46% reported diarrhea.4 GI illnesses can last from 2 days to weeks or longer,5 disrupting plans during travel or after returning home. Eighty percent of those who experienced diarrhea during travel treated themselves with medication and 6% sought medical care. METHODS: The Boston Area Travel Medicine Network (BATMN) is a research collaboration of travel clinics in the greater Boston area representing urban-, suburban-, academic-, and university-affiliated facilities. A convenience sample of travelers ≥ 18 years of age attending three BATMN clinics between 2009 and 2011 for pre-travel consultations completed pre-travel surveys, at least one survey weekly during travel, and a post-travel survey 2–4 weeks after return. Travelers were asked to complete a survey at the end of each week of their trip. Institutional review board approvals were obtained at all sites and the Centers for Disease Control and Prevention, and participants provided written informed consent. Information collected included demographic and trip characteristics, vaccines and medications recommended/prescribed before travel, medications taken during travel, dietary practices during travel (consumption of tap water, ice in drinks, unpasteurized dairy products, and salads), symptoms experienced, and impact of illness during and after travel. Vaccinations, prescriptions, and travel health advice given during the pre-travel consultation were recorded by a clinician, and the remainder of the surveys were completed by the traveler. Data were entered into a password-protected database (CS Pro, U.S. Census Bureau, Washington, DC). RESULTS: We enrolled 987 travelers; 628 (64%) completed all three parts (pre-, during, and post-travel) and were included in the study. Comparison of the 628 to the 359 who did not complete all three parts (noncompleters) revealed no differences, except that completion rates were higher for white travelers than all other racial/ethnic groups (P < 0.001) and for older travelers (median age 47 years versus 32 years in noncompleters, P < 0.001).11 Of those 628 travelers, 208 (33%) experienced TD, 45 (7%) experienced non-TD GI symptoms, 147 (23%) experienced non-GI symptoms, and 228 (36%) did not experience any symptoms during or after travel. Of the 208 with TD, 140 (67%) reported diarrhea as their only symptom, whereas 33 (16%) also experienced nausea/vomiting, 23 (11%) abdominal pain, and 27 (13%) fever (Table 1). Of the 45 who reported non-TD GI symptoms, 21 (47%) experienced nausea/vomiting, 19 (42%) experienced constipation, and 10 (22%) experienced abdominal pain during or after travel (Table 2). Almost all travelers (99%) received advice about food and water precautions and diarrhea management during pre-travel consultation

Bioelectronic DNA detection of human papillomaviruses using eSensor™: a model system for detection of multiple pathogens

BACKGROUND: We used human papillomaviruses (HPV) as a model system to evaluate the utility of a nucleic acid, hybridization-based bioelectronic DNA detection platform (eSensor™) in identifying multiple pathogens. METHODS: Two chips were spotted with capture probes consisting of DNA oligonucleotide sequences specific for HPV types. Electrically conductive signal probes were synthesized to be complementary to a distinct region of the amplified HPV target DNA. A portion of the HPV L1 region that was amplified by using consensus primers served as target DNA. The amplified target was mixed with a cocktail of signal probes and added to a cartridge containing a DNA chip to allow for hybridization with complementary capture probes. RESULTS: Two bioelectric chips were designed and successfully detected 86% of the HPV types contained in clinical samples. CONCLUSIONS: This model system demonstrates the potential of the eSensor platform for rapid and integrated detection of multiple pathogens

Inhibitors of SARS-CoV entry--identification using an internally-controlled dual envelope pseudovirion assay.

Severe acute respiratory syndrome-associated coronavirus (SARS-CoV) emerged as the causal agent of an endemic atypical pneumonia, infecting thousands of people worldwide. Although a number of promising potential vaccines and therapeutic agents for SARS-CoV have been described, no effective antiviral drug against SARS-CoV is currently available. The intricate, sequential nature of the viral entry process provides multiple valid targets for drug development. Here, we describe a rapid and safe cell-based high-throughput screening system, dual envelope pseudovirion (DEP) assay, for specifically screening inhibitors of viral entry. The assay system employs a novel dual envelope strategy, using lentiviral pseudovirions as targets whose entry is driven by the SARS-CoV Spike glycoprotein. A second, unrelated viral envelope is used as an internal control to reduce the number of false positives. As an example of the power of this assay a class of inhibitors is reported with the potential to inhibit SARS-CoV at two steps of the replication cycle, viral entry and particle assembly. This assay system can be easily adapted to screen entry inhibitors against other viruses with the careful selection of matching partner virus envelopes

Control of Myoblast Fusion by a Guanine Nucleotide Exchange Factor, Loner, and Its Effector ARF6

AbstractMyoblast fusion is essential for the formation and regeneration of skeletal muscle. In a genetic screen for regulators of muscle development in Drosophila, we discovered a gene encoding a guanine nucleotide exchange factor, called loner, which is required for myoblast fusion. Loner localizes to subcellular sites of fusion and acts downstream of cell surface fusion receptors by recruiting the small GTPase ARF6 and stimulating guanine nucleotide exchange. Accordingly, a dominant-negative ARF6 disrupts myoblast fusion in Drosophila embryos and in mammalian myoblasts in culture, mimicking the fusion defects caused by loss of Loner. Loner and ARF6, which also control the proper membrane localization of another small GTPase, Rac, are key components of a cellular apparatus required for myoblast fusion and muscle development. In muscle cells, this fusigenic mechanism is coupled to fusion receptors; in other fusion-competent cell types it may be triggered by different upstream signals

Risks and Rewards of Advanced Practice Providers in Cardiothoracic Surgery Training: National Survey

Background Changes in healthcare have led to increasing utilization of Advanced Practice Providers (APPs), but their role in Cardiothoracic Surgery (CTS) education remains undefined. This study aimed to analyze the extent of APP utilization on the CTS team, their role within the hierarchy of clinical care, and the impact of PEs on CTS training from the resident perspective. Methods CTS residents’ responses to the 2017 Thoracic Surgery Residents Association (TSRA)/Thoracic Surgery Directors Association (TSDA) In-Service Training Examination (ITE) survey regarding the role of APPs in specific clinical scenarios, and perception of APP contribution to residents’ educational environment were analyzed. Statistical analysis of categorical variables was performed in SPSS using a Fisher’s exact test and Pearson Chi-Square with statistical significance set at p<0.05. Results Response rate was 82.1% (280/341). The median number of employed APPs was 16-20 and 50.4% (n=141) reported 11-25 PEs at their institution. The median forAPPs in the operating room, floor, and intensive care unit was 3, 3, and 2 respectively. Overall impression of APPs was positive in 87.5% (n=245) of respondents, with 47.7% (n=133) being “very positive” and 40.1% being “positive” (n=112). In general, residents reported greater resident involvement in post-operative issues and operative consults and greater APP involvement in floor issues. 72.5% of residents had not missed a surgical opportunity due to APPs while, 9.6% missed an opportunity due to a APP despite being at an appropriate level of training. Of those that reported missed opportunities, 44% were I-6 residents. There were no significant differences in APPs’ operative role based on resident seniority. Conclusions The overall impression of APPs among CTS residents is favorable, and they more commonly are involved assisting on the floor or the operating room. Occasionally, residents report missing a surgical opportunity due to APPs. There is further opportunity to optimize and standardize their role within programs, in order to improve clinical outcomes and enhance the CTS educational experience for residents

Robust superconductivity and the suppression of charge-density wave in Ca3(Ir1−xRhx)4Sn13\text{Ca}_{3}(\text{Ir}_{1-x}\text{Rh}_{x})_{4}\text{Sn}_{13} single crystals at ambient pressure

Single crystals of Ca$_3$(Ir$_{1-x}$Rh$_x$)$_4$Sn$_{13}$ (3-4-13) were synthesized by flux growth and characterized by X-ray diffraction, EDX, magnetization, resistivity and radio frequency magnetic susceptibility tunnel diode resonator (TDR) techniques. Compositional variation of the Rh/Ir ratio was used to study the coexistence and competition between the charge density wave (CDW) and superconductivity. The superconducting transition temperature varies from approximately 7 K in pure Ir ($x=0$) to approximately 8.3 K in pure Rh ($x=1$). Temperature-dependent electrical resistivity reveals monotonic suppression of the CDW transition temperature, $T_{\text{CDW}}(x)$. The CDW starts in pure Ir, $x=0$, with $T_{\text{CDW}}\approx40$~K and extrapolates roughly linearly to zero at $x_c=0.58$ under the dome of superconductivity. Magnetization and transport measurements show a significant influence of CDW on the superconducting and normal state. Vortex pinning is substantially enhanced in the CDW region, and the resistivity is larger in this part of the phase diagram. The London penetration depth is attenuated exponentially upon cooling at low temperatures for all compositions, indicating a fully-gapped Fermi surface. We conclude that a novel $\text{Ca}_3(\text{Ir}_{1-x}\text{Rh}_x)_4\text{Sn}_{13}$ alloy with coexisting/competing CDW and superconductivity, is a good candidate to look for a composition-driven quantum critical point at ambient pressure

N-Terminal Pro–B-Type Natriuretic Peptide in the Emergency Department: The ICON-RELOADED Study

Background Contemporary reconsideration of diagnostic N-terminal pro–B-type natriuretic peptide (NT-proBNP) cutoffs for diagnosis of heart failure (HF) is needed. Objectives This study sought to evaluate the diagnostic performance of NT-proBNP for acute HF in patients with dyspnea in the emergency department (ED) setting. Methods Dyspneic patients presenting to 19 EDs in North America were enrolled and had blood drawn for subsequent NT-proBNP measurement. Primary endpoints were positive predictive values of age-stratified cutoffs (450, 900, and 1,800 pg/ml) for diagnosis of acute HF and negative predictive value of the rule-out cutoff to exclude acute HF. Secondary endpoints included sensitivity, specificity, and positive (+) and negative (−) likelihood ratios (LRs) for acute HF. Results Of 1,461 subjects, 277 (19%) were adjudicated as having acute HF. The area under the receiver-operating characteristic curve for diagnosis of acute HF was 0.91 (95% confidence interval [CI]: 0.90 to 0.93; p < 0.001). Sensitivity for age stratified cutoffs of 450, 900, and 1,800 pg/ml was 85.7%, 79.3%, and 75.9%, respectively; specificity was 93.9%, 84.0%, and 75.0%, respectively. Positive predictive values were 53.6%, 58.4%, and 62.0%, respectively. Overall LR+ across age-dependent cutoffs was 5.99 (95% CI: 5.05 to 6.93); individual LR+ for age-dependent cutoffs was 14.08, 4.95, and 3.03, respectively. The sensitivity and negative predictive value for the rule-out cutoff of 300 pg/ml were 93.9% and 98.0%, respectively; LR− was 0.09 (95% CI: 0.05 to 0.13). Conclusions In acutely dyspneic patients seen in the ED setting, age-stratified NT-proBNP cutpoints may aid in the diagnosis of acute HF. An NT-proBNP <300 pg/ml strongly excludes the presence of acute HF