Search

Computational protein design is advancing rapidly. Here we describe efficient routes starting from validated parallel and antiparallel peptide assemblies to design two families of α-helical barrel proteins with central channels that bind small molecules. Computational designs are seeded by the sequences and structures of defined de novo oligomeric barrel-forming peptides, and adjacent helices are connected by loop building. For targets with antiparallel helices, short loops are sufficient. However, targets with parallel helices require longer connectors; namely, an outer layer of helix–turn–helix–turn–helix motifs that are packed onto the barrels. Throughout these computational pipelines, residues that define open states of the barrels are maintained. This minimizes sequence sampling, accelerating the design process. For each of six targets, just two to six synthetic genes are made for expression in Escherichia coli. On average, 70% of these genes express to give soluble monomeric proteins that are fully characterized, including high-resolution structures for most targets that match the design models with high accuracy.

We implement and interpret various supervised learning experiments involving real quadratic fields with class numbers 1, 2 and 3. We quantify the relative difficulties in separating class numbers of matching/different parity from a data-scientific perspective, apply the methodology of feature analysis and principal component analysis, and use symbolic classification to develop machine-learned formulas for class numbers 1, 2 and 3 that apply to our dataset.

Dual-emission fluorescence probes that provide high sensitivity are key for biomedical diagnostic applications. Nontoxic carbon dots (CDs) are an emerging alternative to traditional fluorescent probes; however, robust and reproducible synthetic strategies are still needed to access materials with controlled emission profiles and improved fluorescence quantum yields (FQYs). Herein, we report a practical and general synthetic strategy to access dual-emission CDs with FQYs as high as 0.67 and green/blue, yellow/blue, or red/blue excitation-dependent emission profiles using common starting materials such as citric acid, cysteine, and co-dopants to bias the synthetic pathway. Structural and physicochemical analysis using nuclear magnetic resonance, absorbance and fluorescence spectroscopy, Fourier-transform infrared spectroscopy, and X-ray photoelectron spectroscopy in addition to transmission electron and atomic force microscopy (TEM and AFM) is used to elucidate the material’s composition which is responsible for the unique observed photoluminescence properties. Moreover, the utility of the probes is demonstrated in the clinical setting by the synthesis of green/blue emitting antibody-CD conjugates which are used for the immunohistochemical staining of human brain tissues of glioblastoma patients, showing detection under two different emission channels.

Despite many decades of study, the excited state photophysics of polyenes remains controversial. In diphenylpolyenes with conjugated backbones that contain between 2 and 4 double carbon–carbon bonds, the first two excited electronic states are nearly degenerate but of entirely different character, and their energy splitting is strongly dependent on solvent polarizability. To examine the interplay between these different states, steady-state and time-resolved fluorescence spectroscopies were used to undertake a comprehensive investigation of diphenylocatetraene’s (DPO) excited state dynamics in 10 solvents of different polarizabilities and polarities, ranging from weakly interacting alkanes to polar hydrogen-bonding alcohols. These data revealed that photopreparation of the optically bright 1Bustate resulted in fast (<170 ps) internal conversion to the lower-lying optically dark 2Agstate. The 2Agstate is responsible for almost all the observed DPO fluorescence and gains oscillator strength via vibronic intensity stealing with the near-degenerate 1Bustate. The fluorescence lifetime associated with the 2Agstate decayed monoexponentially (4.2–7.2 ns) in contrast to prior biexponential decay kinetics reported for similar polyenes, diphenylbutadiene and diphenylhexatriene. An analysis combining the measured fluorescence lifetimes and fluorescence quantum yields (the latter varying between 7 and 21%) allowed for a 190 cm–1Herzberg–Teller vibronic coupling constant between the 1Buand 2Agstates to be determined. The analysis also revealed that the ordering of electronic states remains constant in all the solvents studied, with the 2Agstate minimum always lower in energy than that of the 1Bustate, thus making it a relatively simple polyene compared to structurally similar diphenylhexatriene.

Effective planning, controlling, and decision making are necessary to identify and avert problems that can limit success and contribute to business failure. Within favorable economic climates, businesses can survive despite [...]

The 2014–2017 global coral bleaching event caused widespread coral mortality; however, its impact on the capacity for coral reefs to maintain calcium carbonate structures has not been determined. Here, we quantified remotely sensed maximum heat stress during the 2014–2017 bleaching event, census‐based net carbonate budgets from benthic imagery and fish survey data, and net reef calcification from salinity normalized seawater total alkalinity anomalies collected from 2017–2019 for 56 Pacific coral reef sites (Mariana Islands, Northwestern Hawaiian Islands, Pacific Remote Island Areas, and American Samoa). We incorporated the census‐based and chemistry‐based metrics to determine a calcification vulnerability index for each site to maintain calcium carbonate balance to provide accessible information to managers and policy makers. Most coral reef sites likely experienced ecologically severe (79%, n= 44) or significant (9%, n= 7) heat stress during the 2014–2017 coral bleaching event. Census‐based net carbonate budgets (mean ± 95% = 2.1 ± 0.6 kg CaCO3m−2yr−1) were positive for 77% of sites (n= 43), neutral for 16% of sites (n= 9), and negative for 7% of sites (n= 4). Chemistry‐based relative net reef calcification (mean ± 95% = 22 ± 10 μmol kg−1) was positive for 84% of sites (n= 47), neutral for 11% of sites (n= 6), and negative for 5% of sites (n= 3). The calcification vulnerability index suggested the Pacific Ocean reef sites surveyed were of minimal (68%, n= 38) to moderate (32%, n= 18) concern for maintaining calcium carbonate balance following the bleaching event. This suggests that many reefs maintained positive calcium carbonate balance, but that a large number of reefs may be approaching a potential threshold for maintaining their calcium carbonate balance under the climate crisis.

Objectives. To examine the impact of a Wisconsin health care reform enacted in early 2008 on public insurance enrollment and retention. Data Sources. Administrative data covering the period January 2007 to November 2009. Study Design. We calculate unadjusted enrollment trends and exit rates stratified by age, income group, and enrollment mode. Kaplan-Meier curves and Cox proportional hazards models are estimated to assess the impact of the reform on program exits. Principal Findings. Overall enrollment increased by approximately one-third and exit rates decreased by approximately one-fifth. The majority of new enrollment came from the previously income eligible. Conclusions. Wisconsin's enactment of eligibility expansions coupled with administrative simplification and targeted marketing and outreach efforts were successful in enrolling and retaining low-income children and families in public coverage. Key Words. Medicaid expansions, health care reform, health insurance, Wisconsin's BadgerCare Plus (BC+) program was designed to ensure access to health insurance coverage to virtually all Wisconsin children and to bolster coverage for parents and other caretaker adults. The [...]

BACKGROUND. Pancreatic ductal adenocarcinoma (PDAC) is still a challenge with poor prognosis. As the disease progresses, new genetic changes may occur leading to more aggressive and less treatment responsive cells, [...]

This article examines the role of the California Health Benefits Review Program (CHBRP) as a source of information in state health policy making. It explains why the California benefits review process relies heavily on university-based researchers and employs a broad set of criteria for review, which set it apart from similar programs in other states. It then analyzes the politics of health insurance mandates and how independent research and analysis might alter the perceived benefits and costs of health insurance mandates and thus political outcomes. It considers how research and analysis is typically used by policy makers, and illustrates how participants inside and outside of state government have used the reports prepared by CHBRP as both guidance in policy design and as political ammunition. Although there is consensus that the review process has reduced the number of mandate bills that are passed out of the legislature, both supporters and opponents favor the new process and generally believe the reports strengthen their case in legislative debates over health insurance mandates. The role of the CHBRP is narrowly defined by statute at the present time, but the program may well face pressure to evolve from its current academic orientation into a more interactive, advisory role for legislators in the future. Key Words. State health policy, health insurance, politics, legislative decision making, The great significance of the growing role of experts in the democratic process is not, as is often feared, their ability to manipulate elected representatives and gain irresponsible control over [...]

Pharmacogenomics is a pillar of personalized medicine that has the potential to deliver optimized treatment in many medical settings. Military medicine in the deployed setting is unique and therefore warrants separate assessment pertaining to its potential capabilities and impact. Pharmacogenomics for United States Active Duty Service Members medical care in the deployed setting has not, to our knowledge, been previously reviewed. We present potential applications of pharmacogenomics to forward medical care through two comprehensive references for deployed medical care, the Tactical Combat Casualty Care Guidelines (TCCC) and Emergency War Surgery (EWS) fifth edition. All drugs within the deployment manuals, TCCC guidelines and EWS book, were identified and the list was cross-referenced to the Clinical Pharmacogenetics Implementation Consortium guidelines and genes–drugs interactions list as well as the Food and Drug Administration Table of Pharmacogenomics Biomarkers in Drug Labeling. Ten pharmacologic categories were identified, consisting of 15 drugs, along with the classes, aminogylcosides, beta-blockers, and volatile anesthetics. Drugs and pharmacogenomics liabilities were tabulated. Eight specific drugs or classes are expounded upon given the belief of the authors of their potential for impacting future treatment on the battlefield in the setting of prolonged field care. This review outlines several genes with liabilities in the prolonged field care setting and areas that may produce improved care with further study.

Pharmacogenomics (PGx) plays a fundamental role in personalized medicine, providing an evidence-based treatment approach centered on the relationship between genomic variations and their effect on drug metabolism. Cytochrome P450 (CYP450) enzymes are responsible for the metabolism of most clinically prescribed drugs and a major source of variability in drug pharmacokinetics and pharmacodynamics. To assess the prevalence of PGx testing within the Military Health System (MHS), testing of specific CYP450 enzymes was evaluated. Data were retrospectively obtained from the Military Health System Management Analysis and Reporting Tool (M2) database. Patient demographics were identified for each test, along with TRICARE status, military treatment facility, clinic, and National Provider Identifier. A total of 929 patients received 1,833 PGx tests, predominantly composed of active duty/guard service members (N= 460; 49.5%), with highest testing rates in the army (51.5%). An even distribution in testing was observed among gender, with the highest rates in Caucasians (41.7%). Of the CYP enzymes assessed, CYP2C19 and CYP2D6 accounted for 87.8% of all PGx CYP testing. The majority of patients were tested in psychiatry clinics (N= 496; 53.4%) and primary care clinics (N= 233; 25.1%), accounting for 56.4% and 24.8% of all tests, respectively. Testing was found to be provider driven, suggesting a lack of a standardized approach to PGx and its application in patient care within the MHS. We initially recommend targeted education and revising testing labels to be more uniform and informative. Long-term recommendations include establishing pharmacy-driven protocols and point-of-care PGx testing to optimize patient outcomes.

Starting from the zygote, all cells in the human body continuously acquire mutations. Mutations shared between different cells imply a common progenitor and are thus naturally occurring markers for lineage tracing1,2. Here we reconstruct extensive phylogenies of normal tissues from three adult individuals using whole-genome sequencing of 511 laser capture microdissections. Reconstructed embryonic progenitors in the same generation of a phylogeny often contribute to different extents to the adult body. The degree of this asymmetry varies between individuals, with ratios between the two reconstructed daughter cells of the zygote ranging from 60:40 to 93:7. Asymmetries pervade subsequent generations and can differ between tissues in the same individual. The phylogenies resolve the spatial embryonic patterning of tissues, revealing contiguous patches of, on average, 301 crypts in the adult colonic epithelium derived from a most recent embryonic cell and also a spatial effect in brain development. Using data from ten additional men, we investigated the developmental split between soma and germline, with results suggesting an extraembryonic contribution to primordial germ cells. This research demonstrates that, despite reaching the same ultimate tissue patterns, early bottlenecks and lineage commitments lead to substantial variation in embryonic patterns both within and between individuals.

Over the course of an individual’s lifetime, normal human cells accumulate mutations1. Here we compare the mutational landscape in 29 cell types from the soma and germline using multiple samples from the same individuals. Two ubiquitous mutational signatures, SBS1 and SBS5/40, accounted for the majority of acquired mutations in most cell types, but their absolute and relative contributions varied substantially. SBS18, which potentially reflects oxidative damage2, and several additional signatures attributed to exogenous and endogenous exposures contributed mutations to subsets of cell types. The rate of mutation was lowest in spermatogonia, the stem cells from which sperm are generated and from which most genetic variation in the human population is thought to originate. This was due to low rates of ubiquitous mutational processes and may be partially attributable to a low rate of cell division in basal spermatogonia. These results highlight similarities and differences in the maintenance of the germline and soma.

The cellular landscape of the human intestinal tract is dynamic throughout life, developing in utero and changing in response to functional requirements and environmental exposures. Here, to comprehensively map cell lineages, we use single-cell RNA sequencing and antigen receptor analysis of almost half a million cells from up to 5 anatomical regions in the developing and up to 11 distinct anatomical regions in the healthy paediatric and adult human gut. This reveals the existence of transcriptionally distinct BEST4 epithelial cells throughout the human intestinal tract. Furthermore, we implicate IgG sensing as a function of intestinal tuft cells. We describe neural cell populations in the developing enteric nervous system, and predict cell-type-specific expression of genes associated with Hirschsprung’s disease. Finally, using a systems approach, we identify key cell players that drive the formation of secondary lymphoid tissue in early human development. We show that these programs are adopted in inflammatory bowel disease to recruit and retain immune cells at the site of inflammation. This catalogue of intestinal cells will provide new insights into cellular programs in development, homeostasis and disease.

A newspaper wishing to cover big events, such as the Olympic games, needs to come out with a strategy that involves every department editor and publishing news stories about the event days ahead of its scheduled launching. In this way, coverage would be complete as every aspect ranging from concerts and ticket sales to the weather could be written about. Furthermore, the advance news helps generate reader interest.

Global concern over widely documented declines in pollinators1–3has led to the identification of anthropogenic stressors that, individually, are detrimental to bee populations4–7. Synergistic interactions between these stressors could substantially amplify the environmental effect of these stressors and could therefore have important implications for policy decisions that aim to improve the health of pollinators3,8,9. Here, to quantitatively assess the scale of this threat, we conducted a meta-analysis of 356 interaction effect sizes from 90 studies in which bees were exposed to combinations of agrochemicals, nutritional stressors and/or parasites. We found an overall synergistic effect between multiple stressors on bee mortality. Subgroup analysis of bee mortality revealed strong evidence for synergy when bees were exposed to multiple agrochemicals at field-realistic levels, but interactions were not greater than additive expectations when bees were exposed to parasites and/or nutritional stressors. All interactive effects on proxies of fitness, behaviour, parasite load and immune responses were either additive or antagonistic; therefore, the potential mechanisms that drive the observed synergistic interactions for bee mortality remain unclear. Environmental risk assessment schemes that assume additive effects of the risk of agrochemical exposure may underestimate the interactive effect of anthropogenic stressors on bee mortality and will fail to protect the pollinators that provide a key ecosystem service that underpins sustainable agriculture.

Tracing produced water origins from wells hydraulically fractured with freshwater-based fluids is sometimes predicated on assumptions that (1) each geological formation contains compositionally unique brine and (2) produced water from recently hydraulically fractured wells resembles fresher meteoric water more so than produced water from older wells. These assumptions are not valid in Williston Basin oil wells sampled in this study. Although distinct average 228Ra/226Ra ratios were found in water produced from the Bakken and Three Forks Formations, average δ2H, δ18O, specific gravity, and conductivity were similar but exhibited significant variability across five oil fields within each formation. Furthermore, initial produced water (“flowback”) was operationally defined based on the presence of glycol ether compounds and water from wells that had produced <56% of the amount of fluids injected and sampled within 160 days of fracturing. Flowback unexpectedly exhibited higher temperature, specific gravity, conductivity, δ2H, and δ18O, but lower oxidation–reduction potential and δ11B, relative to the wells thought to be producing formation brines (from wells with a produced-to-injected water ratio [PIWR] > 0.84 and sampled more than 316 days after fracturing). As such, establishing an overall geochemical and isotopic signature of produced water compositions based solely on chemical similarity to meteoric water and formation without the consideration of well treatments, well completion depth, or lateral location across the basin could be misleading if these signatures are assumed to be applicable across the entire basin. These findings have implications for using produced water compositions to understand the interbasin fluid flow and trace sources of hydraulic fracturing fluids.

ABSTRACTIntroductionThe fibroblast growth factor receptor (FGFR) pathway is essential in cell proliferation, differentiation, migration, and survival. Cancers such as intrahepatic cholangiocarcinoma (IHCA) have demonstrated alterations of FGFR allowing unregulated growth. Infigratinib (BGJ398) is a potent ATP-competitive inhibitor of all four FGFR receptors as demonstrated by the consistently high prevalence of hyperphosphatemia, indicating disruption of FGFR-related phosphate homeostasis.Areas coveredIn this article, the authors discuss preclinical studies and the biological characterization of BGJ398 that inspired its investigation for cancer treatment. They summarize results from phase I and II studies and comment on ongoing phase III clinical trials primarily focusing on its role in treating IHCA.Expert opinionInfigratinib exhibits high potency FGFR1-3 inhibition in preclinical studies. Clinically, agents targeting FGFR including infigratinib show promising anti-tumor activity in targeted trials. Pemigatinib, an FGFR inhibitor, has recently been approved by the FDA for use in refractory IHCA. We believe infigratinib represents a promising agent in the treatment of refractory IHCA with FGFR2 fusions and is uniquely positioned to be a potential option in chemonaive patient populations. An ongoing phase III trial (PROOF-301) compares the efficacy and safety of infigratinib versus standard gemcitabine and cisplatin in untreated patients with IHCA and FGFR2 fusions.

The photochemical dynamics of three classes of organic photoredox catalysts employed in organocatalyzed atom-transfer radical polymerization (O-ATRP) are studied using time-resolved optical transient absorption and fluorescence spectroscopy. The nine catalysts selected for study are examples of N-aryl and core-substituted dihydrophenazine, phenoxazine and phenothiazine compounds with varying propensities for control of polymerization outcomes. Excited singlet-state lifetimes extracted from the spectroscopic measurements are reported in N,N-dimethylformamide (DMF), dichloromethane (DCM), and toluene. Ultrafast (<200 fs to 3 ps) electronic relaxation of the photocatalysts after photoexcitation at near-UV wavelengths (318–390 nm) populates the first singlet excited state (S1). The S1-state lifetimes range from 130 ps to 40 ns with a considerable dependence on the photocatalyst structure and the solvent. The competition between ground electronic state recovery and intersystem crossing controls triplet state populations and is a minor pathway in the dihydrophenazine derivatives but is of greater importance for phenoxazine and phenothiazine catalysts. A comparison of our results with previously reported O-ATRP performances of the various photoredox catalysts shows that high triplet-state quantum yields are not a prerequisite for controlling polymer dispersity. For example, the photocatalyst 5,10-bis(4-cyanophenyl)-5,10-dihydrophenazine, shown previously to exert good polymerization control, possesses the shortest S1-state lifetime (135 ps in DMF and 180 ps in N,N-dimethylacetamide) among the nine examples reported here and a negligible triplet-state quantum yield. The results call for a re-evaluation of the excited-state properties of most significance in governing the photocatalytic behavior of organic photoredox catalysts in O-ATRP reactions.

A 'sense of touch' and error recovery routines contribute to reliability. Data capture, error injection, and mechanical regression testing facilities improved the productivity of the designers. THE SERVOMECHANISM OF THE […]

Placentas can exhibit chromosomal aberrations that are absent from the fetus1. The basis of this genetic segregation, which is known as confined placental mosaicism, remains unknown. Here we investigated the phylogeny of human placental cells as reconstructed from somatic mutations, using whole-genome sequencing of 86 bulk placental samples (with a median weight of 28 mg) and of 106 microdissections of placental tissue. We found that every bulk placental sample represents a clonal expansion that is genetically distinct, and exhibits a genomic landscape akin to that of childhood cancer in terms of mutation burden and mutational imprints. To our knowledge, unlike any other healthy human tissue studied so far, the placental genomes often contained changes in copy number. We reconstructed phylogenetic relationships between tissues from the same pregnancy, which revealed that developmental bottlenecks genetically isolate placental tissues by separating trophectodermal lineages from lineages derived from the inner cell mass. Notably, there were some cases with full segregation—within a few cell divisions of the zygote—of placental lineages and lineages derived from the inner cell mass. Such early embryonic bottlenecks may enable the normalization of zygotic aneuploidy. We observed direct evidence for this in a case of mosaic trisomic rescue. Our findings reveal extensive mutagenesis in placental tissues and suggest that mosaicism is a typical feature of placental development.

Personalized medicine is the right treatment, to the right patient, at the right dose. Knowledge of genetic predisposition to variable metabolism and distribution of drugs within the body is currently available as pharmacogenomic testing and is one of the pillars of personalized medicine. Pharmacogenomic testing is growing. It has become part of guidelines for dosing on FDA labels and has been used by health care organizations to improve outcomes and reduce adverse events. Additionally, it has been FDA approved for direct-to-consumer purchase and has been cause of concern of patient self-dosing and medication changes. Presumably in the near future, pharmacogenomics will be impressed upon the military health system (MHS) provider from either a top-down, command requested, or from a bottom-up, patient requested, approach. To date, widespread implementation of pharmacogenomic testing does not seem to be established within the MHS. This survey sheds light on the knowledge, exposure, use, comfort, and interest among family medicine providers in the MHS. It compares similar results in other national and international surveys and compares results among a small subset of residents to staff.

We must pull our heads out of the sand The "biggest of the big" storms Some of the largest events in the record have been particularly destructive, for example the storm in June 2016 where a residential swimming pool washed onto the beach at Narrabeen-Collaroy. This beach has sufficient sand to enable recovery after extreme storm events such as those experienced in the La Niña period of 1974-78. [Extracted from the article]

The benefits and disadvantages of starting graduate medical education in the fourth year of medical school was recently discussed at a conference sponsored by the American Board of Pediatrics Foundation. Although such a program has been started at three universities, the American Board of Pediatrics will not credit graduate medical training given before completion of medical school. Medical students enrolled in a fourth year medical school graduate training program are paid a first-year resident stipend. In the 1970s, efforts were made to increase the number of medical student graduates. Medical schools were given $2,000 for each medical student, and funds were used to either increase class sizes or to graduate students early, providing them with an income. Funds were also used to develop medical education programs. However, these funds were cut, ending the three-year medical school program. A survey revealed that neither students nor faculty approved of the program. An early internship program initiated in 1970 at Duke University also failed because of student restrictions on training at other institutions and adverse interactions between classmates. The early internship program is designed to reduce student debt; attract students into the fields of internal medicine and family practice; and improve clinical education. Other areas discussed include medical licensure procedures and the United States Medical Licensure Examination. Improvements in clinical education programs are generally preferred over the early internship programs. (Consumer Summary produced by Reliance Medical Information, Inc.)

Coral reef calcification is expected to decline due to climate change stressors such as ocean acidification and warming. Projections of future coral reef health are based on our understanding of the environmental drivers that affect calcification and dissolution. One such driver that may impact coral reef health is heterotrophy of oceanic‐sourced particulate organic matter, but its link to calcification has not been directly investigated in the field. In this study, we estimated net ecosystem calcification and oceanic particulate organic carbon (POCoc) uptake across the Kāne'ohe Bay barrier reef in Hawai'i. We show that higher rates of POCocuptake correspond to greater net ecosystem calcification rates, even under low aragonite saturation states (Ωar). Hence, reductions in offshore productivity may negatively impact coral reefs by decreasing the food supply required to sustain calcification. Alternatively, coral reefs that receive ample inputs of POCocmay maintain higher calcification rates, despite a global decline in Ωar. Coral reefs are threatened by climate change stressors including ocean acidification and ocean warming. One way to measure and monitor coral reef health is to estimate coral reef calcification, which is influenced by several environmental factors including light, temperature, pH, and nutrient availability. By understanding the effects of these factors on calcification, we can better predict how corals will respond to climate change. One potentially important factor for calcification that has not been investigated in the field is coral reef ecosystem feeding on particulate organic matter supplied from offshore (i.e., oceanic particulate organic matter). In this study, we estimated net ecosystem calcification and oceanic particulate organic carbon (POC) uptake across the Kāne'ohe Bay barrier reef in Hawai'i. For the first time, we show a direct correlation between net ecosystem calcification and oceanic POC uptake, which suggests that the reef is using oceanic POC as an energy source to elevate calcification. However, since climate change reduces oceanic POC production through warming and stratification, our results imply coral reef calcification may decline. Alternatively, coral reefs located in regions of high oceanic productivity and that sustain greater rates of oceanic POC uptake may be able to maintain calcification longer into the future. Oceanic particulate organic matter uptake elevates net ecosystem calcification, even under low aragonite saturation statesThe rates of net ecosystem calcification and oceanic particulate organic matter uptake are sensitive to changes in water flow speeds

The ultrafast dynamics of a bimolecular excited-state proton transfer (ESPT) reaction between the photoacid 7-hydroxy-4-(trifluoromethyl)-1-coumarin (CouOH) and 1-methylimidazole (MI) base in aprotic chloroform-d1solution were investigated using ultrafast transient infrared (TRIR) and transient absorption (TA) spectroscopies. The excited-state lifetime of the photoacid in solution is relatively short (52 ps), which at the millimolar photoacid and base concentrations used in our study precludes any diffusion-controlled bimolecular ESPT reactions. This allows the prompt ESPT reaction between hydrogen-bonded CouOH and MI molecules to be studied in isolation and the “contact” ESPT dynamics to be unambiguously determined. Our time-resolved studies reveal that ultrafast ESPT from the CouOH moiety to hydrogen-bonded MI molecules occurs within ∼1 ps, tracked by unequivocal spectroscopic signatures of CouO–* photoproducts that are formed in tandem with HMI+. Some of the ESPT photoproducts subsequently π-stack to form exciplexes on a ∼35 ps time scale, minimizing the attractive Coulombic forces between the oppositely charged aromatic molecules. For the concentrations of CouOH and MI used in our study (up to 8 mM), we saw no evidence for excited-state tautomerization of coumarin anions.

Background: While the number of internal medicine-pediatrics (med/peds) residency training programs has increased considerably in the past decade, questions continue to be raised about career paths of the graduates of these programs. It is uncertain whether med/peds graduates follow a generalist career path and whether they continue to practice both specialties. Objective: To determine the career outcomes of graduates of med/peds residency programs. Design: A survey questionnaire of graduates of med/ peds residency programs. Methods: The computer databases of the American Board of Pediatrics and the American Board of Internal Medicine were used to identify 1482 individuals who had completed training in combined med/peds residency programs between 1986 and 1995 and who had applied to either board for certification. The survey questionnaire was mailed to all graduates identified. Main Outcome Measures: Time spent in professional activity (patient care, teaching, administration, and research), site of principal clinical activity, ages of the patient population, types of hospital privileges, practice organization, subspecialty activity, night and weekend coverage arrangements, community size of practice, involvement in teaching, and membership in professional organizations. Results: Of the total group of 1482 graduates, 87.3% are certified by the American Board of Internal Medicine, 91.3% by the American Board of Pediatrics, and 81.6% by both boards. The survey was completed by 1005 graduates (67.8%). The principal activity of almost 70% of the graduates was direct patient care. Most graduates cared for patients of all ages. More than half of all respondents noted that their principal clinical site is a community office practice. Eighty-five percent managed patients who require hospitalization. Approximately 50% of respondents had a medical school appointment. Conclusions: This study, the largest survey to date of med/ peds graduates, provides strong evidence that most med/ peds graduates are practicing generalists who care for adults and children. In addition, the fact that 80% of graduates achieve dual board certification suggests that these physicians are well qualified to care for the spectrum of health care needs of children and adults. Because the changing US health care system mandates a strong primary care base, these physicians will play a small but important role in providing high-quality generalist care. Arch Pediatr Adolesc Med. 1999;153:823-828, Most pediatric medicine graduates have become general practitioners, caring for both adults and children, and some 80% of them are board certified for both fields. This is significant because the United States health care system is strongly based in primary care. A survey was done of all graduates who completed pediatric medicine residency programs between 1986 and 1995. The survey was completed by 1,005 graduates of the total 1,482. Nearly 70% were practicing direct care of patients, most for patients of all ages, 85% managed patients who require hospitalization, and approximately 50% had a medical school appointment.

The study of channel margin deposits is crucial to better understand fluvial systems and has significant social and economic implications. This paper describes sedimentological features of Late Holocene levee and point-bar deposits from five excellent outcrop exposures along the Cambodian tract of the Mekong River. Point-bar deposits show a typical fining-upward trend with low-angle inclined bedding and consist of gravelly sand, sand and mud beds. Levee deposits show a typical coarsening-upward or no clear vertical grain-size trend and consist of mud and very fine sand beds. Channel margin deposits formed in the outer river bend show a simple levee element, whereas inner bend deposits show more complex architecture with combinations of point-bar and levee elements. Water-level fluctuations play a fundamental role in the construction of point-bar and levee architecture; the resulting deposits show evidence of strong river currents with rapid sedimentation alternating with evidence of subaerial exposure with no sedimentation. This combination of sedimentary features can also form in other environments, but is distinctive of channel margin deposits forming in climates with a pronounced seasonality, including large and perennial rivers in tropical savannah climate areas. [ABSTRACT FROM AUTHOR]

The article by Abenhaim and colleagues in this issue presents an interesting case-control study that attempts to determine the risk of ovarian cancer associated with health care use by comparing [...]

A 32-year-old male developed neuropsychiatric symptoms 2 weeks after starting mefloquine 250 mg/week for malaria prophylaxis. He continued to take the medication for the next 4 months. Initial symptoms included vivid dreams and anxiety, as well as balance problems. These symptoms persisted and progressed over the next 4 years to include vertigo, emotional lability, and poor short-term memory, which have greatly affected his personal and professional life. An extensive evaluation revealed objective evidence supporting a central vestibulopathy. These symptoms have been unresponsive to pharmacologic therapy and psychotherapy. A Naranjo assessment score of 6 was obtained for his initial symptoms, indicating a probable adverse drug reaction to mefloquine given the relationship between the clinical picture and drug exposure.

Background. Translational research seeks to build bridges between research and practice to address public health issues efficiently and effectively. The purpose of this article was to evaluate a newly formed institute that provided graduate students and adolescent behavioral health community professionals with a translational research service-learning opportunity through the creation of a community–university mentoring partnership. Goals of the team-based research mentorship approach included (1) providing students the skills for implementing translational research, (2) providing research opportunities for community agencies to enhance operations and to encourage ongoing research involvement, and (3) developing relationships between university faculty and community agency professionals for further research collaborations. Method. The Institute used the National Institute on Drug Abuse’s Mentoring Mosaic to select a diverse group of community and academic mentors. The research mentorship experience of the initial cohort was evaluated based on the Research Mentorship Conceptual Framework and Self-Assessment Tool. Results. As a direct result of the research mentorship, outcomes for the academic and community mentors and scholars (i.e., those seeking a graduate certificate) included improved working relationships/networking and research experience. Through experiential learning, scholars also discovered career trajectory clarity, the need for community collaboration in research, opportunities for continuing professional development, a greater understanding of public health competencies and how they align with community-based research, and skill development in best practices for translational research. Conclusion. The team mentoring approach is a form of pedagogy that holds promise to enhance translational research and community-based research efforts while developing public health competencies.

The reactions of niobium cluster cations, Nb+n(n= 2–19), with nitric oxide have been investigated using Fourier transform ion cyclotron resonance mass spectrometry (FT-ICR). The overall reaction rate constants are found to be in reasonable agreement with collision rates calculated using the surface charge capture model. The dominant reaction for small clusters (n< 9) involves reaction-induced fragmentation resulting in the loss of either NbO or NbN. By contrast, the main reaction observed for the larger clusters (n> 11) is sequential NO chemisorption. Clusters n= 9, 10 exhibit both extremes of behaviour and are the only clusters upon which there is evidence of NO decomposition with N2loss observed whenever multiple NO molecules are co-adsorbed. The rate constants for each process have been determined as a function of cluster size.

Introduction: Patients with coronavirus disease 2019 (COVID-19) have an increased risk for venous thromboembolic events. Thrombotic events contribute to the morbidity and mortality associated with COVID-19 infection, and have prompted investigation into strategies for mitigating thrombosis risk in patients hospitalized with COVID-19 infection. Our team reviewed the charts of patients hospitalized with COVID-19 pneumonia at a tertiary hospital in metropolitan Phoenix Arizona between 2020-2021, to assess frequency and efficacy of utilizing a VTE prophylaxis algorithm designed to prevent thrombosis in patients infected with COVID-19.

A comprehensive field survey was conducted, and a numerical model based on the Princeton Ocean Model was established to investigate the vertical structure of current induced by surface waves and identify its effect on sand loss from a beach. Previous studies have examined wave‐induced longshore transport, whereas this study focused on cross‐shore transport caused by waves. The introduction of vertically dependent radiation stress revealed that wave‐induced vertical gyres existed with onshore and offshore flows in the upper and lower layers, respectively, besides the well‐known wave‐induced longshore flow. It was found that the vertical gyres were caused by the onshore wave force (a gradient of radiation stress) in the upper layer and the offshore wave force usually existed in the lower layer, as well as the horizontal imbalance of local wave force. The locations of wave‐induced vertical gyres were found to correspond to the location of sediment erosion, and thus the lower part of the vertical gyres drove the offshore transport of eroded sediment. Moreover, the vertical gyres were located in areas with a highly variable topographic gradient (e.g., at a bar), and their driven offshore currents (undertow/return flow) extended far beyond the surf zone. The topographic slope had a profound effect on the vertical structure. Numerical experiments showed that an extended breakwater from the eastern headland of the bay could prevent sediment from being eroded. Furthermore, the shear front at the rim of a horizontal gyre could retain suspended sediment in the center of the gyre. Rather than examining longshore flow, which has been extensively investigated, this study focused on cross‐shore flow due to waves. It was found that in addition to the longshore flow (vertically mean), a wave‐induced offshore flow component extended a long‐distance offshore. Moreover, the vertical and horizontal gyres (eddies) generated by waves greatly contributed to sand loss from a beach. Specifically, a vertical gyre eroded sediment and drove its offshore transport in the lower layer of water. Furthermore, it was determined that the vertical and horizontal gyres were both affected by highly variable topographic slopes, and that the fast‐rotating rim of a horizontal gyre ensured that suspended sediment was retained in the center of the gyre. The results suggest that a breakwater extending from the eastern headland could prevent the erosion of sediment in the bay, as simulations showed that the pattern of wave‐induced currents was mainly influenced by the length of barriers (headlands) and the bottom slope. In addition to vertically mean longshore flow, there was a prevalent wave‐induced offshore component of flowWave‐induced vertical gyres were found to erode sediment and drive its offshore transportNumerical experiments showed that a breakwater at the eastern headland of the bay could prevent the erosion of sediment In addition to vertically mean longshore flow, there was a prevalent wave‐induced offshore component of flow Wave‐induced vertical gyres were found to erode sediment and drive its offshore transport Numerical experiments showed that a breakwater at the eastern headland of the bay could prevent the erosion of sediment

To investigate the role of self-sampling for human papillomavirus (HPV) testing as an alternative to cervical cancer screening by clinicians (i.e., Papanicolaou [Pap] test).

To develop clinical practice guidelines for cervical screening and the primary management of abnormal cytology in Ontario, using an established methodological process.

The use of 3D scanning systems for the capture and measurement of human body dimensions is becoming commonplace. While the ability of available scanning systems to record the surface anatomy of the human body is generally regarded as acceptable for most applications, effective use of the images to obtain anthropometric data requires specially developed data extraction software. However, for large data sets, extraction of useful information can be quite time consuming. A major benefit therefore is to possess an automated software program that quickly facilitates the extraction of reliable anthropometric data from 3D scanned images. In this paper the accuracy and variability of two fully automated data extraction systems (Cyberware WB-4 scanner with Natick-Scan software and Hamamatsu BL Scanner with accompanying software) are examined and compared with measurements obtained from traditional anthropometry. In order to remove many confounding variables that living humans introduce during the scanning process, a set of clothing dressforms was chosen as the focus of study. An analysis of the measurement data generally indicates that automated data extraction compares favorably with standard anthropometry for some measurements but requires additional refinement for others.

Prologue:California has long been a battleground in the struggle to reform the traditional relationship between patients, payers, and providers. Many of the reform issues—particularly whether government should mandate employers to provide health insurance to their workers—that are now before Congress have been the subject of previous debates in California. In this paper Tom Oliver and Emery Dowell depict these struggles and how they were resolved or left untended. Oliver and Dowell underscore one of the realities about American democracy—that private interests play a critical role in shaping public policy. Oliver, who holds a doctorate in political science from the University of North Carolina, is an assistant professor in the Policy Sciences Graduate Program at the University of Maryland, Baltimore County. The Robert Wood Johnson Foundation recently bestowed on Oliver one of its Investigator Awards in Health Policy Research. Dowell is a retired vice-president for governmental affairs of Blue Cross of California. This paper draws upon his experience working among health care interest groups as an honest broker (or, as he put it in a telephone conversation, “a legendary nuisance”) in an effort to craft a compromise solution to California's insurance access problem. Dowell helped to draft and promote the 1989 health insurance reform legislation sponsored by Assembly Speaker Willie Brown, the legislature's most powerful figure, and also consulted with the California Medical Association and the insurance industry. Dowell is a member of the California Managed Risk Medical Insurance Board, which designed the first statewide, government-sponsored, regional health insurance purchasing pool for small groups (see Health Affairs, Spring I 1994, page 350).Abstract:We review the 1992 policy choices in California for expanding health insurance coverage, focusing on the rejection of an employer mandate by legislators and voters. We analyze how interest-group politics, gubernatorial politics, and national politics shaped those choices. Although public opinion and the shift of organized medicine showed considerable support for extending health insurance coverage, the opposition of liberal and conservative groups and a foundering economy prevented a significant change in public policy. The president's health reform plan appears to address many of the unresolved concerns in California, but overcoming resistance to any kind of mandate will require skilled leadership and negotiation.