Infected pancreatic necrosis: outcomes and clinical predictors of mortality. A post hoc analysis of the MANCTRA-1 international study

: The identification of high-risk patients in the early stages of infected pancreatic necrosis (IPN) is critical, because it could help the clinicians to adopt more effective management strategies. We conducted a post hoc analysis of the MANCTRA-1 international study to assess the association between clinical risk factors and mortality among adult patients with IPN. Univariable and multivariable logistic regression models were used to identify prognostic factors of mortality. We identified 247 consecutive patients with IPN hospitalised between January 2019 and December 2020. History of uncontrolled arterial hypertension (p = 0.032; 95% CI 1.135-15.882; aOR 4.245), qSOFA (p = 0.005; 95% CI 1.359-5.879; aOR 2.828), renal failure (p = 0.022; 95% CI 1.138-5.442; aOR 2.489), and haemodynamic failure (p = 0.018; 95% CI 1.184-5.978; aOR 2.661), were identified as independent predictors of mortality in IPN patients. Cholangitis (p = 0.003; 95% CI 1.598-9.930; aOR 3.983), abdominal compartment syndrome (p = 0.032; 95% CI 1.090-6.967; aOR 2.735), and gastrointestinal/intra-abdominal bleeding (p = 0.009; 95% CI 1.286-5.712; aOR 2.710) were independently associated with the risk of mortality. Upfront open surgical necrosectomy was strongly associated with the risk of mortality (p < 0.001; 95% CI 1.912-7.442; aOR 3.772), whereas endoscopic drainage of pancreatic necrosis (p = 0.018; 95% CI 0.138-0.834; aOR 0.339) and enteral nutrition (p = 0.003; 95% CI 0.143-0.716; aOR 0.320) were found as protective factors. Organ failure, acute cholangitis, and upfront open surgical necrosectomy were the most significant predictors of mortality. Our study confirmed that, even in a subgroup of particularly ill patients such as those with IPN, upfront open surgery should be avoided as much as possible. Study protocol registered in ClinicalTrials.Gov (I.D. Number NCT04747990)

Burnout among surgeons before and during the SARS-CoV-2 pandemic: an international survey

Background: SARS-CoV-2 pandemic has had many significant impacts within the surgical realm, and surgeons have been obligated to reconsider almost every aspect of daily clinical practice. Methods: This is a cross-sectional study reported in compliance with the CHERRIES guidelines and conducted through an online platform from June 14th to July 15th, 2020. The primary outcome was the burden of burnout during the pandemic indicated by the validated Shirom-Melamed Burnout Measure. Results: Nine hundred fifty-four surgeons completed the survey. The median length of practice was 10 years; 78.2% included were male with a median age of 37 years old, 39.5% were consultants, 68.9% were general surgeons, and 55.7% were affiliated with an academic institution. Overall, there was a significant increase in the mean burnout score during the pandemic; longer years of practice and older age were significantly associated with less burnout. There were significant reductions in the median number of outpatient visits, operated cases, on-call hours, emergency visits, and research work, so, 48.2% of respondents felt that the training resources were insufficient. The majority (81.3%) of respondents reported that their hospitals were included in the management of COVID-19, 66.5% felt their roles had been minimized; 41% were asked to assist in non-surgical medical practices, and 37.6% of respondents were included in COVID-19 management. Conclusions: There was a significant burnout among trainees. Almost all aspects of clinical and research activities were affected with a significant reduction in the volume of research, outpatient clinic visits, surgical procedures, on-call hours, and emergency cases hindering the training. Trial registration: The study was registered on clicaltrials.gov "NCT04433286" on 16/06/2020

Cooperative Anion Recognition in Copper(II) and Zinc(II) Complexes with a Ditopic Tripodal Ligand Containing a Urea Group

The ability of Cu^II and Zn^II complexes of the ditopic receptor H₂L [1-(2-((bis­(pyridin-2-ylmethyl)­amino)­methyl)­phenyl)-3-(3-nitrophenyl)­urea] for anion recognition is reported. In the presence of weakly coordinating anions such as ClO₄^–, the urea group binds to the metal ion (Cu^II or Zn^II) through one of its nitrogen atoms. The study of the interaction of the metal complexes with a variety of anions in DMSO shows that SO₄^2– and Cl^– bind to the complexes through a cooperative binding involving simultaneous coordination to the metal ion and different hydrogen-bonding interactions with the urea moiety, depending on the shape and size of the anion. On the contrary, single crystal X-ray diffraction studies show that anions such as NO₃^– and PhCO₂^– form 1:2 complexes (metal/anion) where one of the anions coordinates to the metal center and the second one is involved in hydrogen-bonding interaction with the urea group, which is projected away from the metal ion. Spectrophotometric titrations performed for the Cu^II complex indicate that this system is able to bind a wide range of anions with an affinity sequence: MeCO₂^– ∼ Cl^– (log <i>K</i>₁₁ > 7) > NO₂^– > H₂PO₄^– ∼ Br^– > HSO₄^– > NO₃^– (log <i>K</i>₁₁ < 2). In contrast to this, the free ligand gives much weaker interactions with these anions. In the presence of basic anions such as MeCO₂^– or F^–, competitive processes associated with the deprotonation of the coordinated N–H group of the urea moiety take place. Thus, N-coordination of the urea unit to the metal ion increases the acidity of one of its N–H groups. DFT calculations performed in DMSO solution are in agreement with both an anion-hydrogen bonding interaction and an anion–metal ion coordination collaborating in the stabilization of the metal salt complexes with tetrahedral anions

Cooperative Anion Recognition in Copper(II) and Zinc(II) Complexes with a Ditopic Tripodal Ligand Containing a Urea Group

The ability of Cu^II and Zn^II complexes of the ditopic receptor H₂L [1-(2-((bis­(pyridin-2-ylmethyl)­amino)­methyl)­phenyl)-3-(3-nitrophenyl)­urea] for anion recognition is reported. In the presence of weakly coordinating anions such as ClO₄^–, the urea group binds to the metal ion (Cu^II or Zn^II) through one of its nitrogen atoms. The study of the interaction of the metal complexes with a variety of anions in DMSO shows that SO₄^2– and Cl^– bind to the complexes through a cooperative binding involving simultaneous coordination to the metal ion and different hydrogen-bonding interactions with the urea moiety, depending on the shape and size of the anion. On the contrary, single crystal X-ray diffraction studies show that anions such as NO₃^– and PhCO₂^– form 1:2 complexes (metal/anion) where one of the anions coordinates to the metal center and the second one is involved in hydrogen-bonding interaction with the urea group, which is projected away from the metal ion. Spectrophotometric titrations performed for the Cu^II complex indicate that this system is able to bind a wide range of anions with an affinity sequence: MeCO₂^– ∼ Cl^– (log <i>K</i>₁₁ > 7) > NO₂^– > H₂PO₄^– ∼ Br^– > HSO₄^– > NO₃^– (log <i>K</i>₁₁ < 2). In contrast to this, the free ligand gives much weaker interactions with these anions. In the presence of basic anions such as MeCO₂^– or F^–, competitive processes associated with the deprotonation of the coordinated N–H group of the urea moiety take place. Thus, N-coordination of the urea unit to the metal ion increases the acidity of one of its N–H groups. DFT calculations performed in DMSO solution are in agreement with both an anion-hydrogen bonding interaction and an anion–metal ion coordination collaborating in the stabilization of the metal salt complexes with tetrahedral anions

Solution Structure of Ln(III) Complexes with Macrocyclic Ligands Through Theoretical Evaluation of ¹H NMR Contact Shifts

Herein, we present a new approach that combines DFT calculations and the analysis of Tb^III-induced ¹H NMR shifts to quantitatively and accurately account for the contact contribution to the paramagnetic shift in Ln^III complexes. Geometry optimizations of different Gd^III complexes with macrocyclic ligands were carried out using the hybrid meta-GGA TPSSh functional and a 46 + 4f⁷ effective core potential (ECP) for Gd. The complexes investigated include [Ln­(Me-DODPA)]⁺ (H₂Me-DODPA = 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid, [Ln­(DOTA)­(H₂O)]⁻ (H₄DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), [Ln­(DOTAM)­(H₂O)]³⁺ (DOTAM = 1,4,7,10- tetrakis­[(carbamoyl)­methyl]-1,4,7,10-tetraazacyclododecane), and related systems containing pyridyl units (Ln = Gd, Tb). Subsequent all-electron relativistic calculations based on the DKH2 approximation, or small-core ECP calculations, were used to compute the ¹H hyperfine coupling constants (HFCCs) at the ligand nuclei (<i>A</i>_iso values). The calculated <i>A</i>_iso values provided direct access to contact contributions to the ¹H NMR shifts of the corresponding Tb^III complexes under the assumption that Gd and Tb complexes with a given ligand present similar HFCCs. These contact shifts were used to obtain the pseudocontact shifts, which encode structural information as they depend on the position of the nucleus with respect to the lanthanide ion. An excellent agreement was observed between the experimental and calculated pseudocontact shifts using the DFT-optimized geometries as structural models of the complexes in solution, which demonstrates that the computational approach used provides (i) good structural models for the complexes, (ii) accurate HFCCs at the ligand nuclei. The methodology presented in this work can be classified in the context of model-dependent methods, as it relies on the use of a specific molecular structure obtained from DFT calculations. Our results show that spin polarization effects dominate the ¹H <i>A</i>_iso values. The X-ray crystal structures of [Ln­(Me-DODPA)]­(PF₆)·2H₂O (Ln = Eu or Lu) are also reported

Solution Structure of Ln(III) Complexes with Macrocyclic Ligands Through Theoretical Evaluation of ¹H NMR Contact Shifts

Herein, we present a new approach that combines DFT calculations and the analysis of Tb^III-induced ¹H NMR shifts to quantitatively and accurately account for the contact contribution to the paramagnetic shift in Ln^III complexes. Geometry optimizations of different Gd^III complexes with macrocyclic ligands were carried out using the hybrid meta-GGA TPSSh functional and a 46 + 4f⁷ effective core potential (ECP) for Gd. The complexes investigated include [Ln­(Me-DODPA)]⁺ (H₂Me-DODPA = 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid, [Ln­(DOTA)­(H₂O)]⁻ (H₄DOTA = 1,4,7,10-tetraazacyclododecane-1,4,7,10-tetraacetate), [Ln­(DOTAM)­(H₂O)]³⁺ (DOTAM = 1,4,7,10- tetrakis­[(carbamoyl)­methyl]-1,4,7,10-tetraazacyclododecane), and related systems containing pyridyl units (Ln = Gd, Tb). Subsequent all-electron relativistic calculations based on the DKH2 approximation, or small-core ECP calculations, were used to compute the ¹H hyperfine coupling constants (HFCCs) at the ligand nuclei (<i>A</i>_iso values). The calculated <i>A</i>_iso values provided direct access to contact contributions to the ¹H NMR shifts of the corresponding Tb^III complexes under the assumption that Gd and Tb complexes with a given ligand present similar HFCCs. These contact shifts were used to obtain the pseudocontact shifts, which encode structural information as they depend on the position of the nucleus with respect to the lanthanide ion. An excellent agreement was observed between the experimental and calculated pseudocontact shifts using the DFT-optimized geometries as structural models of the complexes in solution, which demonstrates that the computational approach used provides (i) good structural models for the complexes, (ii) accurate HFCCs at the ligand nuclei. The methodology presented in this work can be classified in the context of model-dependent methods, as it relies on the use of a specific molecular structure obtained from DFT calculations. Our results show that spin polarization effects dominate the ¹H <i>A</i>_iso values. The X-ray crystal structures of [Ln­(Me-DODPA)]­(PF₆)·2H₂O (Ln = Eu or Lu) are also reported

Stabilizing Divalent Europium in Aqueous Solution Using Size-Discrimination and Electrostatic Effects

We report two macrocyclic ligands containing a 1,10-diaza-18-crown-6 fragment functionalized with either two picolinamide pendant arms (bpa18c6) or one picolinamide and one picolinate arm (ppa18c6^–). The X-ray structure of [La­(ppa18c6)­(H₂O)]²⁺ shows that the ligand binds to the metal ion using the six donor atoms of the crown moiety and the four donor atoms of the pendant arms, 11-coordination being completed by the presence of a coordinated water molecule. The X-ray structure of the [Sr­(bpa18c6)­(H₂O)]²⁺ was also investigated due to the very similar ionic radii of Sr²⁺ and Eu²⁺. The structure of this complex is very similar to that of [La­(ppa18c6)­(H₂O)]²⁺, with the metal ion being 11-coordinated. Potentiometric measurements were used to determine the stability constants of the complexes formed with La³⁺ and Eu³⁺. Both ligands present a very high selectivity for the large La³⁺ ion over the smaller Eu³⁺, with a size-discrimination ability that exceeds that of the analogous ligand containing two picolinate pendant arms reported previously (bp18c6^2–). DFT calculations using the TPSSh functional and the large-core pseudopotential approximation provided stability trends in good agreement with the experimental values, indicating that charge neutral ligands derived from 1,10-diaza-18-crown-6 enhance the selectivity of the ligand for the large Ln³⁺ ions. Cyclic voltammetry measurements show that the stabilization of Eu²⁺ by these ligands follows the sequence bp18c6^2– < ppa18c6^– < bpa18c6 with half-wave potentials of −753 mV (bp18c6^2–), −610 mV (ppa18c6^–), and −453 mV (bpa18c6) versus Ag/AgCl. These values reveal that the complex of bpa18c6 possesses higher stability against oxidation than the aquated ion, for which an <i>E</i>_1/2 value of −585 mV has been measured

Lanthanide(III) Complexes with Ligands Derived from a Cyclen Framework Containing Pyridinecarboxylate Pendants. The Effect of Steric Hindrance on the Hydration Number

Two new macrocyclic ligands, 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂DODPA) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb­(DODPA)]­(PF₆)·H₂O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (<i>q</i>) obtained from luminescence lifetime measurements in aqueous solution of the Eu^III and Tb^III complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H₂Me-DODPA are <i>q</i> = 0. The structure of the complexes in solution has been investigated by ¹H and ¹³C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb^III complex [Λ­(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb^III-induced paramagnetic ¹H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd­(Me-DODPA)]⁺ are typical of a complex with <i>q</i> = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd­(DODPA)]⁺ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature ¹⁷O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd­(DODPA)]⁺. The results show that this system is endowed with a relatively fast water exchange rate <i>k</i>_<i>ex</i>²⁹⁸ = 58 × 10⁶ s^–1

Lanthanide(III) Complexes with Ligands Derived from a Cyclen Framework Containing Pyridinecarboxylate Pendants. The Effect of Steric Hindrance on the Hydration Number

Two new macrocyclic ligands, 6,6′-((1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂DODPA) and 6,6′-((4,10-dimethyl-1,4,7,10-tetraazacyclododecane-1,7-diyl)­bis­(methylene))­dipicolinic acid (H₂Me-DODPA), designed for complexation of lanthanide ions in aqueous solution, have been synthesized and studied. The X-ray crystal structure of [Yb­(DODPA)]­(PF₆)·H₂O shows that the metal ion is directly bound to the eight donor atoms of the ligand, which results in a square-antiprismatic coordination around the metal ion. The hydration numbers (<i>q</i>) obtained from luminescence lifetime measurements in aqueous solution of the Eu^III and Tb^III complexes indicate that the DODPA complexes contain one inner-sphere water molecule, while those of the methylated analogue H₂Me-DODPA are <i>q</i> = 0. The structure of the complexes in solution has been investigated by ¹H and ¹³C NMR spectroscopy, as well as by theoretical calculations performed at the density functional theory (DFT; mPWB95) level. The minimum energy conformation calculated for the Yb^III complex [Λ­(λλλλ)] is in good agreement with the experimental structure in solution, as demonstrated by the analysis of the Yb^III-induced paramagnetic ¹H shifts. The nuclear magnetic relaxation dispersion (NMRD) profiles recorded for [Gd­(Me-DODPA)]⁺ are typical of a complex with <i>q</i> = 0, where the observed relaxivity can be accounted for by the outer-sphere mechanism. However, [Gd­(DODPA)]⁺ shows NMRD profiles consistent with the presence of both inner- and outer-sphere contributions to relaxivity. A simultaneous fitting of the NMRD profiles and variable temperature ¹⁷O NMR chemical shifts and transversal relaxation rates provided the parameters governing the relaxivity in [Gd­(DODPA)]⁺. The results show that this system is endowed with a relatively fast water exchange rate <i>k</i>_<i>ex</i>²⁹⁸ = 58 × 10⁶ s^–1

Mono‑, Bi‑, and Trinuclear Bis-Hydrated Mn²⁺ Complexes as Potential MRI Contrast Agents

We report a series of ligands containing pentadentate 6,6′-((methylazanediyl)­bis­(methylene))­dipicolinic acid binding units that form mono- (H₂dpama), di- (<i>m</i>X­(H₂dpama)₂), and trinuclear (<i>m</i>X­(H₂dpama)₃) complexes with Mn²⁺ containing two coordinated water molecules per metal ion, which results in pentagonal bipyramidal coordination around the metal ions. In contrast, the hexadentate ligand 6,6′-((ethane-1,2-diylbis­(azanediyl))­bis­(methylene))­dipicolinic acid (H₂bcpe) forms a complex with distorted octahedral coordination around Mn²⁺ that lacks coordinated water molecules. The protonation constants of the ligands and the stability constants of the Mn²⁺, Cu²⁺, and Zn²⁺ complexes were determined using potentiometric and spectrophotometric titrations in 0.15 M NaCl. The pentadentate dpama^2– ligand and the di- and trinucleating mX­(dpama)₂^4– and mX­(dpama)₃^6– ligands provide metal complexes with stabilities that are very similar to that of the complex with the hexadentate ligand bcpe^2–, with log β₁₀₁ values in the range 10.1–11.6. Cyclic voltammetry experiments on aqueous solutions of the [Mn­(bcpe)] complex reveal a quasireversible system with a half-wave potential of +595 mV versus Ag/AgCl. However, [Mn­(dpama)] did not suffer oxidation in the range 0.0–1.0 V, revealing a higher resistance toward oxidation. A detailed ¹H NMRD and ¹⁷O NMR study provided insight into the parameters that govern the relaxivity for these systems. The exchange rate of the coordinated water molecules in [Mn­(dpama)] is relatively fast, <i>k</i>_ex²⁹⁸ = (3.06 ± 0.16) × 10⁸ s^–1. The trinuclear [mX­(Mn­(dpama)­(H₂O)₂)₃] complex was found to bind human serum albumin with an association constant of 1286 ± 55 M^–1 and a relaxivity of the adduct of 45.2 ± 0.6 mM^–1 s^–1 at 310 K and 20 MHz