Thiopurine methyltransferase (TPMT) activity exhibits a monogenic codominant inheritance and catabolizes thiopurines. TPMT variant alleles are associated with low enzyme activity and pronounced ...pharmacologic effects of thiopurines. Loss‐of‐function alleles in the NUDT15 gene are common in Asians and Hispanics and reduce the degradation of active thiopurine nucleotide metabolites, also predisposing to myelosuppression. We provide recommendations for adjusting starting doses of azathioprine, mercaptopurine, and thioguanine based on TPMT and NUDT15 genotypes (updates on www.cpicpgx.org).
Mentorship is a key component in preventing burnout and attrition in surgical training, yet many residencies lack a formal program, one method used to establish successful mentor relationships. We ...aimed to measure the difference in resident perceptions and experience after the implementation of a mentorship program.
An anonymous survey was distributed to all general surgery residents at a single academic institution before and after implementation of a year-long mentorship program that involved assigned mentors, two social events, and recommended mentorship meetings. Responses were recorded on a five-point Likert scale.
Half of respondents (n = 17, 53%) attended at least one event, and 66% (n = 21) had at least one mentor meeting. The proportion of residents who identified a faculty mentor increased from 59% to 75%. Residents with two or more mentor meetings (n = 12, 38%) were more likely to report faculty were interested in mentoring and cared about their development (3.5 versus 4.6, 3.6 versus 4.6, P < 0.001). They were more likely to identify faculty approachable for resident performance (3.8 versus 4.6, P < 0.02) and outside of work concerns (3.2 versus 4.3, P < 0.01) and were more likely to be satisfied with the amount of mentorship received (2.8 versus 4.0 P < 0.001).
Implementation of a formal mentorship program resulted in an improvement in resident perception of faculty involvement and support. Meeting with a mentor resulted in a significant improvement in resident perception. Implementation of a mentorship program can improve resident experience, and few interactions are needed to affect the change.
Abstract
Tuberculosis (TB), caused by Mycobacterium tuberculosis (Mtb), remains a major public health problem. Household contact studies identify children and adults along the spectrum from Mtb ...exposure to disease. In the Kawempe Community Health Study (conducted in Kampala, Uganda), 872 culture-confirmed pulmonary TB cases and their 2,585 contacts were enrolled during 2002–2012 and followed for up to 2 years each. Risk factors identified by time-to-event analysis for secondary TB differed among children, women, and men. Younger age (P = 0.0061), human immunodeficiency virus (HIV) (P = 0.0002), thinness (P = 0.01), absent bacille Calmette-Guérin vaccination (P = 0.002), and epidemiologic risk score (P < 0.0001) were risks for children. For women, risks were HIV (P < 0.0001), thinness (World Health Organization criteria; P < 0.0001), and epidemiologic risk score (P = 0.003). For men, HIV (P = 0.0007) and low body mass index (P = 0.008) resulted in faster progression to TB. Tuberculin skin testing (TST) identified contacts with Mtb infection and those with persistently negative TST. Risks for faster time to Mtb infection were identified, and included age (P = 0.0007), baseline TST induration (P < 0.0001), and epidemiologic risk score (P < 0.0001) only in children. Those with persistently negative TST comprised 10% of contacts but had no unique epidemiologic characteristics among adults. The burden of Mtb infection and disease is high in TB households, and risk factors for progression from exposure to infection and disease differ among children, women, and men.
We consider the Ising model on a dense Erdős–Rényi random graph,
G
(
N
,
p
)
, with
p
>
0
fixed—equivalently, a disordered Curie–Weiss Ising model with
Ber
(
p
)
couplings—at zero temperature. The ...disorder may induce local energy minima in addition to the two uniform ground states. In this paper we prove that, starting from a typical initial configuration, the zero-temperature dynamics avoids all such local minima and absorbs into a predetermined one of the two uniform ground states. We relate this to the local MINCUT problem on dense random graphs; namely with high probability, the greedy search for a local MINCUT of
G
(
N
,
p
)
with
p
>
0
fixed, started from a uniform random partition, fails to find a non-trivial cut. In contrast, in the disordered Curie–Weiss model with heavy-tailed couplings, we demonstrate that zero-temperature dynamics has positive probability of absorbing in a random local minimum different from the two homogenous ground states.
Reductions in tuberculosis (TB) incidence require identification of individuals at high risk of developing active disease, such as those with recent 'Mycobacterium tuberculosis' (Mtb) infection. ...Using a prospective household contact (HHC) study in Kampala, Uganda, we diagnosed new Mtb infection using both the tuberculin skin test (TST) and interferon-gamma release assay (IGRA). Our study aimed to determine if the TST adds additional value to the characterization of IGRA converters. We identified 13 HHCs who only converted the IGRA (QFT-only converters), 39 HHCs who only converted their TST (TST-only converters), and 24 HHCs who converted both tests (QFT/TST converters). Univariate analysis revealed that TST-only converters were older. Additionally, increased odds of TST-only conversion were associated with older age (p equivalent 0.02) and crowdedness (p equivalent 0.025). QFT/TST converters had higher QFT quantitative values at conversion than QFT-only converters and a bigger change in TST quantitative values at conversion than TST-only converters. Collectively, these data indicate that TST conversion alone likely overestimates Mtb infection. Its correlation to older age suggests an "environmental" boosting response due to prolonged exposure to environmental mycobacteria. This result also suggests that QFT/TST conversion May be associated with a more robust immune response, which should be considered when planning vaccine studies.
We consider the complexity of random ferromagnetic landscapes on the hypercube
{
±
1
}
N
given by Ising models on the complete graph with i.i.d. non-negative edge-weights. This includes, in ...particular, the case of Bernoulli disorder corresponding to the Ising model on a dense random graph
G
(
N
,
p
)
. Previous results had shown that, with high probability as
N
→
∞
, the gradient search (energy-lowering) algorithm, initialized uniformly at random, converges to one of the homogeneous global minima (all-plus or all-minus). Here, we devise two modified algorithms tailored to explore the landscape at near-zero magnetizations (where the effect of the ferromagnetic drift is minimized). With these, we numerically verify the landscape complexity of random ferromagnets, finding a diverging number of (1-spin-flip-stable) local minima as
N
→
∞
. We then investigate some of the properties of these local minima (e.g., typical energy and magnetization) and compare to the situation where the edge-weights are drawn from a heavy-tailed distribution.
Fifteen enterobacterial strains were isolated from fresh produce. The 16S rRNA gene sequences indicated that these belong to Serratia, with twelve strains showing 99.57%–99.93% and three strains ...showing 99.86–100% 16S rRNA gene sequence similarity with Serratia marcescens and Serratia nematodiphila as nearest neighbors, respectively. Further comparative multi locus sequence analyses, as well as phylogenomic comparisons, revealed that 6 of the 15 strains were well-separated from their nearest neighbors and formed two clearly distinct taxa. Strains S2, S9, S10 and S15T were urease-positive, while strains S3T and S13 were urease-negative. Average nucleotide identity and digital DNA–DNA hybridization comparisons of representative strains S3T and S15T with type strains of S. marcescens, S. nematodiphila and S. ureilytica indicated that these shared less than 96% and 70% homology, respectively. Major fatty acids of strains S3T and S15T included C16:0, C16:1 ω7c/C16:1 ω6c, C17:0 Cyclo and C18:1 ω6c /C18:1 ω7c. The mol% G+C of genomic DNA of strain S15T was 59.49% and of strain S3T was 59.04. These results support the description of two novel species, Serratia nevei and Serratia bockelmannii, with strains S15T (=LMG 31536T =DSM 110085T) and S3T (=LMG 31535T =DSM 110152T) as type strains, respectively. Although Serratia marcescens subsp. sakuensis was previously described to form spores, spores could not be determined in this study. As spore formation was the only differential characteristic of this subspecies, S. marcescens subsp. sakuensis is a later heterotypic synonym of Serratia marcescens.
Forty-two antibiotic-resistant enterobacteria strains were isolated from fresh produce obtained from the northern German retail market. A polyphasic characterization based on both phenotypic and ...genotypic methods was used to identify predominant strains as Citrobacter (C.) gillenii, C. portucalensis, Enterobacter (En.) ludwigii, Escherichia (E.) coli and Klebsiella (K.) pneumoniae. 38.1% of the enterobacteria strains were resistant to tetracycline, while 23.8% and 9.5% of strains were resistant to streptomycin and chloramphenicol, respectively. A high percentage of Klebsiella (100%), Enterobacter (57.1%) and Citrobacter (42.9%) strains were also resistant to ampicillin, with some strains showing multiple resistances. For unequivocal species identification, the genomes of thirty strains were sequenced. Multilocus sequence analysis, average nucleotide identity and digital DNA–DNA hybridization showed that Enterobacter strains E1 and E13 were clearly clustered apart from Enterobacter species type strains below the species delineation cutoff values. Thus, strains E1T (=DSM 111347T, LMG 31875T) represents a novel species proposed as Enterobacter dykesii sp. nov., while strain E13T (=DSM 110788T, LMG 31764T) represent a novel species proposed as Enterobacter vonholyi sp. nov. Strains often possessed different serine β-lactamase genes, tet(A) and tet(D) tetracycline resistance genes and other acquired antibiotic resistance genes. Typical plasmid replicon types were determined. This study thus accurately identified the enterobacteria from fresh produce as species belonging to the genera Citrobacter, Enterobacter, Escherichia and Klebsiella, but also showed that these can carry potentially transferable antibiotic resistance genes and may thus contribute to the spread of these via the food route.
The geochemical record for the Permian–Triassic boundary in northern latitudes is essential to evaluation of global changes associated with the most profound extinction of life on Earth. We present ...inorganic and organic geochemical data, and Re–Os isotope systematics in a critical stratigraphic interval of pre- and post-extinction Upper Permian–Lower Triassic sediments from Opal Creek, western Canada (paleolatitude of ∼30°N). We document significant and long-lived changes in Panthalassa seawater chemistry that were initiated during the first of four magmatic or meteoritic inputs to Late Permian seawater, evidenced by notable decreases of Os isotopic ratios upsection.
Geochemical signals indicate establishment of anoxic bottom waters shortly after regional transgression reinitiated sedimentation in the Late Permian. Euxinic signals are most prominent in the Upper Permian sediments with low organic carbon and high sulfur contents, and gradually wane in the Lower Triassic. The observed features may have been generated in a strongly euxinic ocean in which high bacterioplankton productivity sustained prolific microbial sulfate reduction in the sediment and/or water column, providing hydrogen sulfide to form pyrite. This scenario requires nearly complete anaerobic decomposition of predominantly labile marine organic matter (OM) without the necessity for a complete collapse of primary marine productivity. Similar geochemical variations could have been achieved by widespread oxidation of methane by sulfate reducers after a methanogenic burst in the Late Permian. Both scenarios could have provided similar kill mechanisms for the latest Permian mass extinction.
Despite the moderate thermal maturity of the section, OM in all studied samples is dominantly terrestrial and/or continentally derived, recycled and refractory ancient OM. We argue that, as such, the quantity of the OM in the section mainly reflects changes in terrestrial vegetation and/or weathering, and not in marine productivity. At Opal Creek, a pyrite layer and <20-cm-thick siltstones that are lean in OM mark dramatic and long-lived inorganic geochemical and stable isotope changes. Initial Os isotope ratios decline markedly toward values of ∼0.35 in the pyrite interval, indicating a mantle-sourced or meteoritic trigger for the intensification and expansion of latest Permian anoxia. Subsequent and stronger magmatic or meteoritic pulses recorded by low initial Os isotopes followed the main extinction.
Picornaviruses are small RNA viruses that hijack host cell machinery to promote their replication. During infection, these viruses express two proteases, 2Apro and 3Cpro, which process viral ...proteins. They also subvert a number of host functions, including innate immune responses, host protein synthesis, and intracellular transport, by utilizing poorly understood mechanisms for rapidly and specifically targeting critical host proteins. Here, we used proteomic tools to characterize 2Apro interacting partners, functions, and targeting mechanisms. Our data indicate that, initially, 2Apro primarily targets just two cellular proteins: eukaryotic translation initiation factor eIF4G (a critical component of the protein synthesis machinery) and Nup98 (an essential component of the nuclear pore complex, responsible for nucleocytoplasmic transport). The protease appears to employ two different cleavage mechanisms; it likely interacts with eIF3L, utilizing the eIF3 complex to proteolytically access the eIF4G protein but also directly binds and degrades Nup98. This Nup98 cleavage results in only a marginal effect on nuclear import of proteins, while nuclear export of proteins and mRNAs were more strongly affected. Collectively, our data indicate that 2Apro selectively inhibits protein translation, key nuclear export pathways, and cellular mRNA localization early in infection to benefit viral replication at the expense of particular cell functions.
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