Global disparities in surgeons’ workloads, academic engagement and rest periods: the on-calL shIft fOr geNEral SurgeonS (LIONESS) study

: The workload of general surgeons is multifaceted, encompassing not only surgical procedures but also a myriad of other responsibilities. From April to May 2023, we conducted a CHERRIES-compliant internet-based survey analyzing clinical practice, academic engagement, and post-on-call rest. The questionnaire featured six sections with 35 questions. Statistical analysis used Chi-square tests, ANOVA, and logistic regression (SPSS® v. 28). The survey received a total of 1.046 responses (65.4%). Over 78.0% of responders came from Europe, 65.1% came from a general surgery unit; 92.8% of European and 87.5% of North American respondents were involved in research, compared to 71.7% in Africa. Europe led in publishing research studies (6.6 ± 8.6 yearly). Teaching involvement was high in North America (100%) and Africa (91.7%). Surgeons reported an average of 6.7 ± 4.9 on-call shifts per month, with European and North American surgeons experiencing 6.5 ± 4.9 and 7.8 ± 4.1 on-calls monthly, respectively. African surgeons had the highest on-call frequency (8.7 ± 6.1). Post-on-call, only 35.1% of respondents received a day off. Europeans were most likely (40%) to have a day off, while African surgeons were least likely (6.7%). On the adjusted multivariable analysis HDI (Human Development Index) (aOR 1.993) hospital capacity > 400 beds (aOR 2.423), working in a specialty surgery unit (aOR 2.087), and making the on-call in-house (aOR 5.446), significantly predicted the likelihood of having a day off after an on-call shift. Our study revealed critical insights into the disparities in workload, access to research, and professional opportunities for surgeons across different continents, underscored by the HDI

DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management

Abstract Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma. Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts. Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (ΔAUC = 0.10, 95% CI: 0.03–0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8–7.2, P &lt; 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (ΔAUC = 0.25, 95% CI: 0.22–0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3–11.1, P &lt; 0.001) with clinical implications. Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone. </jats:sec

Transition metal-substituted Dawson anions as chemo- and regio-selective oxygen transfer catalysts for H₂O₂ in the epoxidation of allylic alcohols

Organic-soluble transition metal-substituted Dawson compounds [(n-C₄H₉)₄N]₉[P₂W₁₇O₆₁M(Br)](Mⁿ⁺=Co²⁺,Ni²⁺,Cu²⁺andZn²⁺),[(n-C₄H₉)₄N]7[HP₂W₁₇O₆₁M(Br)](Mⁿ⁺=Cr³⁺,Mn³⁺and Fe³⁺)and[K/(n-C₄H₉)₄N]₁₀₋n[P₂W₁₇O₆₁M(H₂O)](Mⁿ⁺=Ir⁴⁺, Ru³⁺andPd²⁺)have been investigated as oxygen transfer agents for H₂O₂ to a series of primary allylic alcohols to generate epoxides under biphasic reaction conditions (1,2-dichloroethane/H₂O)at 30 or 35°C, such that the effect of variations in the substituted transition metals could be evaluated. The allylic alcohols involved the species R₁R₂CC(R₃)CH₂–OH(where R₁, R₂ and R₃ = H or Me), as well as cyclic(2-cyclohexen-1-ol), bicyclic [(R-)-(−)-myrtenol and (R-)-(−)-nopol] and species with two unsaturated sites (geraniol and nerol). The reactions are highly chemoselective and regioselective. The order of reactivity for the M(II)-substituted species is Pd(II)>Zn(II)>Co(II)>Ni(II),and for M(III) and M(IV) substitution is Mn(III)~Ir(IV)>Fe(III)>Cr(III). The observed orders are consistent with the formation of metal(n+)-alcohol species as part of the reaction mechanism. For the more polarizing Ir(IV), however, Ir(IV)-alcoholate species are likely involved in the mechanism. Formation constants for the Mn(III)and Co(II)-phosphopolyoxotungstate-alcohol species with all of the above alcohols have been evaluated in 1,2-dichloroethane at 25 °C and range from 19.0-3.5 M⁻¹. The most likely transition state involves coordination of the alcohol to the transition metal substituted at the lacunary site, or alkoxide in the case of Ir(IV), along with interaction of the double bond of the alcohol with a peroxogroup located at a W(VI) site adjacent to the substituted transition metal

Molecular-Dynamics Simulations of ELIC—a Prokaryotic Homologue of the Nicotinic Acetylcholine Receptor

The ligand-gated ion channel from Erwinia chrysanthemi (ELIC) is a prokaryotic homolog of the eukaryotic nicotinic acetylcholine receptor (nAChR) that responds to the binding of neurotransmitter acetylcholine and mediates fast signal transmission. ELIC is similar to the nAChR in its primary sequence and overall subunit organization, but despite their structural similarity, it is not clear whether these two ligand-gated ion channels operate in a similar manner. Further, it is not known to what extent mechanistic insights gleaned from the ELIC structure translate to eukaryotic counterparts such as the nAChR. Here we use molecular-dynamics simulations to probe the conformational dynamics and hydration of the transmembrane pore of ELIC. The results are compared with those from our previous simulation of the human α7 nAChR. Overall, ELIC displays increased stability compared to the nAChR, whereas the two proteins exhibit remarkable similarity in their global motion and flexibility patterns. The majority of the increased stability of ELIC does not stem from the deficiency of the models used in the simulations, and but rather seems to have a structural basis. Slightly altered dynamical correlation features are also observed among several loops within the membrane region. In sharp contrast to the nAChR, ELIC is completely dehydrated from the pore center to the extracellular end throughout the simulation. Finally, the simulation of an ELIC mutant substantiates the important role of F246 on the stability, hydration and possibly function of the ELIC channel

Nanosecond-Timescale Conformational Dynamics of the Human α7 Nicotinic Acetylcholine Receptor

We explore the conformational dynamics of a homology model of the human α7 nicotinic acetylcholine receptor using molecular dynamics simulation and analyses of root mean-square fluctuations, block partitioning of segmental motion, and principal component analysis. The results reveal flexible regions and concerted global motions of the subunits encompassing extracellular and transmembrane domains of the subunits. The most relevant motions comprise a bending, hinged at the β10-M1 region, accompanied by concerted tilting of the M2 helices that widens the intracellular end of the channel. Despite the nanosecond timescale, the observations suggest that tilting of the M2 helices may initiate opening of the pore. The results also reveal direct coupling between a twisting motion of the extracellular domain and dynamic changes of M2. Covariance analysis of interresidue motions shows that this coupling arises through a network of residues within the Cys and M2-M3 loops where Phe135 is stabilized within a hydrophobic pocket formed by Leu270 and Ile271. The resulting concerted motion causes a downward shift of the M2 helices that disrupts a hydrophobic girdle formed by 9′ and 13′ residues