Speeding-up the Determination of Protein-Ligand Affinities by STD NMR: The Reduced Data Set STD NMR Approach (rd-STD NMR).

STD NMR spectroscopy is a powerful ligand-observed NMR tool for screening and characterizing the interactions of small molecules and low molecular weight fragments with a given macromolecule, identifying the main intermolecular contacts in the bound state. It is also a powerful analytical technique for the accurate determination of protein-ligand dissociation constants (KD) of medium-to-weak affinity, of interest in the pharmaceutical industry. However, accurate KD determination and epitope mapping requires a long series of experiments at increasing saturation times to carry out a full analysis using the so-called STD NMR build-up curve approach and apply the "initial slopes approximation". Here, we have developed a new protocol to bypass this important limitation, which allows us to obtain initial slopes by using just two saturation times and, hence, to very quickly determine precise protein-ligand dissociation constants by STD NMR.

Phenylbenzothiazole-Based Platinum(II) and Diplatinum(II) and (III) Complexes with Pyrazolate Groups: Optical Properties and Photocatalysis.

Based on 2-phenylbenzothiazole (pbt) and 2-(4-dimethylaminophenyl)benzothiazole (Me2N-pbt), mononuclear [Pt(pbt)(R'2-pzH)2]PF6 (R'2-pzH = pzH 1a, 3,5-Me2pzH 1b, 3,5-iPr2pzH 1c) and diplatinum (PtII-PtII) [Pt(pbt)(µ-R'2pz)]2 (R'2-pz = pz 2a, 3,5-Me2pz 2b, 3,5-iPr2pz 2c) and [Pt(Me2N-pbt)(µ-pz)]2 (3a) complexes have been prepared. In the presence of sunlight, 2a and 3a evolve, in CHCl3 solution, to form the PtIII-PtIII complexes [Pt(R-pbt)(µ-pz)Cl]2 (R = H 4a, NMe2 5a). Experimental and computational studies reveal the negligible influence of the pyrazole or pyrazolate ligands on the optical properties of 1a-c and 2a,b, which exhibit a typical 3IL/3MLCT emission, whereas in 2c the emission has some 3MMLCT contribution. 3a displays unusual dual, fluorescence (1ILCT or 1MLCT/1LC), and phosphorescence (3ILCT) emissions depending on the excitation wavelength. The phosphorescence is lost in aerated solutions due to sensitization of 3O2 and formation of 1O2, whose determined quantum yield is also wavelength dependent. The phosphorescence can be reversibly photoinduced (365 nm, ∼ 15 min) in oxygenated THF and DMSO solutions. In 4a and 5a, the lowest electronic transitions (S1-S3) have mixed characters (LMMCT/LXCT/L'XCT 4a and LMMCT/LXCT/ILCT 5a) and they are weakly emissive in rigid media. The 1O2 generation property of complex 3a is successfully used for the photooxidation of p-bromothioanisol showing its potential application toward photocatalysis.

sp2-Iminosugar azobenzene O-glycosides: Light-sensitive glycosidase inhibitors with unprecedented tunability and switching factors.

The conventional approach to developing light-sensitive glycosidase activity regulators, involving the combination of a glycomimetic moiety and a photoactive azobenzene module, results in conjugates with differences in glycosidase inhibitory activity between the interchangeable E and Z-isomers at the azo group that are generally below one-order of magnitude. In this study, we have exploited the chemical mimic character of sp2-iminosugars to access photoswitchable p- and o-azobenzene α-O-glycosides based on the gluco-configured representative ONJ. Notably, we achieved remarkably high switching factors for glycosidase inhibition, favoring either the E- or Z-isomer depending on the aglycone structure. Our data also indicate a correlation between the isomeric state of the azobenzene module and the selectivity towards α- and ß-glucosidase isoenzymes. The most effective derivative reached over a 103-fold higher inhibitory potency towards human ß-glucocerebrosidase in the Z as compared with the E isomeric form. This sharp contrast is compatible with ex-vivo activation and programmed self-deactivation at physiological temperatures, positioning it as a prime candidate for pharmacological chaperone therapy in Gaucher disease. Additionally, our results illustrate that chemical tailoring enables the engineering of photocommutators with the ability to toggle inhibition between α- and ß-glucosidase enzymes in a reversible manner, thus expanding the versatility and potential therapeutic applications of this approach.

Machine learning algorithms using national registry data to predict loss to follow-up during tuberculosis treatment.

BACKGROUND: Identifying patients at increased risk of loss to follow-up (LTFU) is key to developing strategies to optimize the clinical management of tuberculosis (TB). The use of national registry data in prediction models may be a useful tool to inform healthcare workers about risk of LTFU. Here we developed a score to predict the risk of LTFU during anti-TB treatment (ATT) in a nationwide cohort of cases using clinical data reported to the Brazilian Notifiable Disease Information System (SINAN). METHODS: We performed a retrospective study of all TB cases reported to SINAN between 2015 and 2022; excluding children (< 18 years-old), vulnerable groups or drug-resistant TB. For the score, data before treatment initiation were used. We trained and internally validated three different prediction scoring systems, based on Logistic Regression, Random Forest, and Light Gradient Boosting. Before applying our models we splitted our data into training (~ 80% data) and test (~ 20%) sets, and then compared the model metrics using the test data set. RESULTS: Of the 243,726 cases included, 41,373 experienced LTFU whereas 202,353 were successfully treated. The groups were different with regards to several clinical and sociodemographic characteristics. The directly observed treatment (DOT) was unbalanced between the groups with lower prevalence in those who were LTFU. Three models were developed to predict LTFU using 8 features (prior TB, drug use, age, sex, HIV infection and schooling level) with different score composition approaches. Those prediction scoring systems exhibited an area under the curve (AUC) ranging between 0.71 and 0.72. The Light Gradient Boosting technique resulted in the best prediction performance, weighting specificity and sensitivity. A user-friendly web calculator app was developed ( https://tbprediction.herokuapp.com/ ) to facilitate implementation. CONCLUSIONS: Our nationwide risk score predicts the risk of LTFU during ATT in Brazilian adults prior to treatment commencement utilizing schooling level, sex, age, prior TB status, and substance use (drug, alcohol, and/or tobacco). This is a potential tool to assist in decision-making strategies to guide resource allocation, DOT indications, and improve TB treatment adherence.

EFFECTIVENESS OVER TIME OF THE REVERSE SHOULDER PROSTHESIS FOR ACUTE PROXIMAL HUMERAL FRACTURE.

BACKGROUND: Reverse shoulder arthroplasty (RSA) has proven to be an effective surgical procedure for irreparable rotator cuff tears, comminuted fractures of the proximal humerus and shoulder arthroplasty revision surgeries. We know from the literature that the functional results are good in the short term, but not whether these results remain stable in the long term or, on the contrary, show a deterioration in functionality. OBJECTIVE: This study aims to analyze the functionality, degree of satisfaction, complications, and prosthesis survival at different cut-off points in patients with complex proximal humerus fractures treated with RSA, with a minimum postoperative follow-up of 7 years. MATERIAL AND METHODS: Analytical, longitudinal and prospective observational study of a cohort of patients treated for a fracture of the proximal humerus with PIH. Functional outcome was assessed using the Constant scale and the Constant adjusted for age and gender of the patients. Quality of life was measured using the University of California at Los Angeles Shoulder Assessment scale (UCLA) and the Disability of the Arm, Shoulder and Hand score scale (QuickDASH). In addition, range of motion, pain and radiological variables of loosening, scapular notching and tuberosity consolidation were assessed. RESULTS: Thirty-three patients were included with a mean postoperative follow-up of 8.3 years (range 7-12 years). There was a progressive and significant decrease in Constant score at 5and7years follow-up compared to the baseline assessment 2 years after surgery, although the effect size was not significant. The age- and sex-adjusted Constant as well as the UCLA scale did not show statistically significant variations at follow-up. Both shoulder abduction and anterior shoulder flexion correlated well with the final QuickDASH score. Radiological variables did not influence any of the study outcome variables. CONCLUSION: The functionality and quality of life of patients with complex proximal humerus fractures treated with RSA decreased significantly compared to the 2-year evaluation, although this change was not clinically relevant. Survival of RSA was satisfactory in the medium to long term with a low complication rate.

Antibiotic prescribing patterns in the placement of dental implants in Europe: A systematic review of survey-based studies.

BACKGROUND: The present systematic review aims to investigate the guidelines for prescribing Preventive Antibiotic Therapy (PAT) in the placement of dental implants (DIs) without anatomical constraints in healthy patients by clinicians in Europe and to compare them with current recommendations. MATERIAL AND METHODS: A search was performed in 4 databases: Medline (via PubMed), Web of Science, Scopus, and LILACS. The criteria employed were those described in the PRISMA (Preferred Reporting Items for Systematic Reviews and Meta-Analysis) declaration (PROSPERO Registration number: CRD42022382278). RESULTS: The electronic search identified 10 studies published between 2010 and 2023 that met the established criteria. Overall, 60.8% ± 24.1% of European professionals routinely prescribe PAT, with the most frequent regimen being perioperative (mean= 46.7% ± 24.3%), followed by postoperative PAT only (mean= 20.3% ± 9.7%). CONCLUSIONS: The most commonly prescribed antibiotic both pre- and postoperatively is amoxicillin and, in allergic patients, clindamycin. In Europe, more doses of PAT are being prescribed than suggested by current recommendations. For this reason, more PAT education is needed in educational curricula to promote a more rational use of antibiotics to reduce the occurrence of antimicrobial resistance.

Causes of death in children with congenital Zika syndrome in Brazil, 2015 to 2018: A nationwide record linkage study.

BACKGROUND: Children with congenital Zika syndrome (CZS) have severe damage to the peripheral and central nervous system (CNS), greatly increasing the risk of death. However, there is no information on the sequence of the underlying, intermediate, immediate, and contributing causes of deaths among these children. The aims of this study are describe the sequence of events leading to death of children with CZS up to 36 months of age and their probability of dying from a given cause, 2015 to 2018. METHODS AND FINDINGS: In a population-based study, we linked administrative data on live births, deaths, and cases of children with CZS from the SINASC (Live Birth Information System), the SIM (Mortality Information System), and the RESP (Public Health Event Records), respectively. Confirmed and probable cases of CZS were those that met the criteria established by the Brazilian Ministry of Health. The information on causes of death was collected from death certificates (DCs) using the World Health Organization (WHO) DC template. We estimated proportional mortality (PM%) among children with CZS and among children with non-Zika CNS congenital anomalies (CA) by 36 months of age and proportional mortality ratio by cause (PMRc). A total of 403 children with confirmed and probable CZS who died up to 36 months of age were included in the study; 81.9% were younger than 12 months of age. Multiple congenital malformations not classified elsewhere, and septicemia unspecified, with 18 (PM = 4.5%) and 17 (PM = 4.2%) deaths, respectively, were the most attested underlying causes of death. Unspecified septicemia (29 deaths and PM = 11.2%) and newborn respiratory failure (40 deaths and PM = 12.1%) were, respectively, the predominant intermediate and immediate causes of death. Fetuses and newborns affected by the mother's infectious and parasitic diseases, unspecified cerebral palsy, and unspecified severe protein-caloric malnutrition were the underlying causes with the greatest probability of death in children with CZS (PMRc from 10.0 to 17.0) when compared to the group born with non-Zika CNS anomalies. Among the intermediate and immediate causes of death, pneumonitis due to food or vomiting and unspecified seizures (PMRc = 9.5, each) and unspecified bronchopneumonia (PMRc = 5.0) were notable. As contributing causes, fetus and newborn affected by the mother's infectious and parasitic diseases (PMRc = 7.3), unspecified cerebral palsy, and newborn seizures (PMRc = 4.5, each) were more likely to lead to death in children with CZS than in the comparison group. The main limitations of this study were the use of a secondary database without additional clinical information and potential misclassification of cases and controls. CONCLUSION: The sequence of causes and circumstances involved in the deaths of the children with CZS highlights the greater vulnerability of these children to infectious and respiratory conditions compared to children with abnormalities of the CNS not related to Zika.

An Analytical Solution for Saturable Absorption in Pharmacokinetics Models.

OBJECTIVE: The first-order absorption is a common model used in Pharmacokinetics. The absorption of some drugs follows carrier mediated transport. It has been proposed that the amount of drug available may saturate the transport mechanism resulting in an absorption slower than the one predicted by the first-order model. Saturable absorption has been modeled at the differential equation level by substituting the constant rate absorption by a Hill kinetics absorption. However, its exact solution is so far unknown. The goal of this is to know the exact solution of different Hill kinetic absorption models. METHODS: We start defining different absorption models and increasing then their complexity. The simplest case is the first-order absorption model and the most complex will be a generalized Hill kinetic absorption model. The differential equation of each model is integrated. RESULTS: The complexity of the models their solutions may be not expressed in a close-form, or in term of elementary functions. We obtain and discuss the exact solutions of the different Hill kinetics absorption models. To do that, the solutions are studied according to the possible values of the free parameters of the models. We show the differences between models through simulations. CONCLUSIONS: The knowledge of closed-form solutions allows to illustrate the differences between the different absorption models and minimizes the errors of numerical integration.

cis/trans-[Pt(C∧N)(C≡CR)(CNBut)] Isomers: Synthesis, Photophysical, DFT Studies, and Chemosensory Behavior.

cis/trans Isomerism can be a crucial factor for photophysical properties. Here, we report the synthesis and optical properties of a series of trans- and cis-alkynyl/isocyanide cycloplatinated compounds [Pt(C∧N)(C≡CR)(CNBut)] [R = C6H4-4-OMe 1, 3-C4H3S 2; C∧N = 2-(2,4-difluorophenyl)pyridine (dfppy) (a), 4-(2-pyridyl)benzaldehyde (ppy-CHO) (b)]. The trans-forms do not isomerize thermally in MeCN solution to the cis forms, but upon photochemical irradiation in this medium at 298 K, a variable isomerization to the cis forms was observed. This behavior is in good agreement with the theoretically calculated energy values. The trans/cis configuration, the identity of the cyclometalated, and the alkynyl ligand influence on the absorption and emission properties of the complexes in solution, polystyrene (PS) films, and solid state are reported. All complexes are efficient triplet emitters in all media (except for trans-1a and trans-2a in CH2Cl2 solution at 298 K), with emission wavelengths depending mainly on the cyclometalated ligand in the region 473-490 nm (dfppy), 510-550 (ppy-CHO), and quantum yields (ϕ) ranging from 18.5 to 40.7% in PS films. The combined photophysical data and time-dependent density functional theory calculations (TD-DFT) at the excited-state T1 geometry reveal triplet excited states of 3L'LCT (C≡CR → C∧N)/3IL (C∧N) character with minor 3MLCT contribution. The dfppy (a) complexes show a greater tendency to aggregate in rigid media than the ppy-CHO (b) and the cis with respect to the trans, showing red-shifted structureless bands of 3MMLCT and/or excimer-like nature. Interestingly, trans-1a,2a and cis-1a,2a undergo significant changes in the ultraviolet (UV) and emission spectra with Hg2+ ions enabling their use for sensing of Hg2+ ions in solution. This is clearly shown by the hypsochromic shift and substantial decrease of the low-energy absorption band and an increase of the intensity of the emission in the MeCN solution upon the addition of a solution of Hg(ClO4)2 (1:5 molar ratio). Job's plot analysis estimated a 1:1 stoichiometry in the complexation mode of Hg2+ by trans-2a. The binding constant (log K) calculated for this system from absorption titration data resulted to be 2.56, and the limit of the detection (LOD) was 6.54 × 10-7 M.

Luminescent Anionic Cyclometalated Organoplatinum (II) Complexes with Terminal and Bridging Cyanide Ligand: Structural and Photophysical Properties.

We present the synthesis and characterization of two series of mononuclear heteroleptic anionic cycloplatinated(II) complexes featuring terminal cyanide ligand Q+[Pt(C^N)(p-MeC6H4)(CN)]- [C^N = benzoquinolate (bzq), Q+ = K+ 1 and NBu4+ 4; 2-phenylpyridinate (ppy), Q+ = K+ 2 and NBu4+ 5 and 2-(2,4- difluorophenyl)pyridinate (dfppy), Q+ = K+ 3 and NBu4+ 6] and a series of symmetrical binuclear complexes (NBu4)[Pt2(C^N)2(p-MeC6H4)2(µ-CN)] (C^N = bzq 7, ppy 8, dfppy 9). Compounds 5, 6, and 7-9 were further determined by single-crystal X-ray diffraction. There are no apparent intermolecular Pt···Pt interactions owing to the presence of bulky NBu4+ counterion. Slow crystallization of K[Pt(ppy)(p-MeC6H4)(CN)] 2 in acetone/hexane evolves with formation of yellow crystals, which were identified by single-crystal X-ray diffraction methods as the salt complex {[Pt(ppy)(p-MeC6H4)(CN)]2K3(OCMe2)4(µ-OCMe2)2}[Pt(ppy)(p-MeC6H4)(µ-CN)Pt(ppy)(p-MeC6H4)]·2acetone (10), featuring the binuclear anionic unit 8- neutralized by an hybrid inorganic-organometallic coordination polymer {[Pt(ppy)(p-MeC6H4)(CN)]2K3(OCMe2)4(µ-OCMe2)2}+. The photophysical properties of all compounds were recorded in powder, polystyrene film, and solution states with a quantum yield up to 21% for 9 in the solid state. All complexes displayed bright emission in rigid media, and for the interpretation of their absorption and emission properties, density functional theory (DFT) and time-dependent DFT calculations were applied.

Superparamagnetic iron oxide nanoparticles induce persistent large foci of DNA damage in human melanoma cells post-irradiation.

The synergy of superparamagnetic iron oxide nanoparticles (SPIONs) and ionizing radiation (IR), attributed to reactive oxygen species (ROS) and DNA double-strand breaks (DSBs) increase, was widely investigated in different cancers, but scarcely in melanoma. Herein, SPIONs were evaluated as radiosensitizers in A-375 human melanoma cells. Moreover, the effect of the combined treatment of SPIONs and gamma irradiation (SPIONs-IR) was assessed at the DNA level, where DSBs induction and their repair capacity were studied. SPIONs were synthesized, stabilized by poly(ethylene glycol) methyl ether and physicochemically characterized by high resolution-transmission electron microscopy (HR-TEM), X-ray diffraction and magnetometry and dynamic light scattering. The obtained nanoparticles showing superparamagnetic behavior and low dispersion in shape and sizes were tested in A-375 cells. The intracellular internalization of SPIONs was verified by HR-TEM and quantified by inductively coupled plasma atomic emission spectroscopy. Cells treated with SPIONs exhibited high ROS levels without associated cytotoxicity. Next, a significant radiosensitization in SPIONs-IR vs. control (IR) cells was demonstrated at 1 Gy of gamma radiation. Furthermore, a decreased DSBs repair capacity in SPIONs-IR vs. IR-treated cells was evidenced by the size increase of persistent phosphorylated H2AX foci at 24 h post-irradiation. In conclusion, these nanoparticles show the potential to radiosensitize melanoma cells by the induction of unrepairable DNA damage.

Increased synovial immunohistochemistry reactivity of TGF-ß1 in erosive peripheral psoriatic arthritis.

BACKGROUND: Immune and non-immune cells contribute to the pathology of chronic arthritis, and they can contribute to tissue remodeling and repair as well as disease pathogenesis. The present research aimed to analyze inflammation and bone destruction/regeneration biomarkers in patients with psoriatic arthritis (PsA), rheumatoid arthritis (RA), osteoarthritis (OA), and ankylosing spondylitis (AS). METHODS: Samples were obtained from the inflamed knee of patients with knee arthritis who had been referred for undergoing arthroscopies. The synovial membrane was processed for pathological description, IHC analysis, and quantification of mRNA expression ratio by qRT-PCR. Serum levels of TGF-ß1, IL-23, IL-6, IL-17 A, IL-22, Dkk1, Sclerostin, BMP2, BMP4, Wnt1, and Wnt5a were measured by ELISA. All these data were analyzed and compared with the demographic, clinical, blood tests, and radiological characteristics of the patients. RESULTS: The synovial membrane samples were obtained from 42 patients for IHC, extraction, and purification of RNA for synovial mRNA expression analysis, and serum for measuring protein levels from 38 patients. IHC reactivity for TGF-ß1 in the synovial tissue was higher in patients with psoriatic arthritis (p 0.036) and was positively correlated with IL-17 A (r = 0.389, p = 0.012), and Dkk1 (r = 0.388, p = 0.012). Gene expression of the IL-17 A was higher in PsA patients (p = 0.018) and was positively correlated with Dkk1 (r = 0.424, p = 0.022) and negatively correlated with BMP2 (r = -0.396, p = 0.033) and BMP4 (r = -0.472, p = 0.010). It was observed that IHC reactivity for TGF-ß1 was higher in patients with erosive PsA (p = 0.024). CONCLUSIONS: The IHC reactivity of TGF-ß1 in synovial tissue was higher in patients with erosive psoriatic arthritis, and TGF-ß1 was in relation to higher levels of gene expression of IL-17 A and Dkk1.

A relevant number of patients do not increase their engagement in physical, social and leisure activities at the medium-term after total knee arthroplasty: a prospective cohort study.

PURPOSE: The purpose of this study was to investigate the changes in engagement in physical, leisure and social activities in older adults following primary TKA. METHODS: A prospective study of 106 patients with a mean age of 72.6 (SD 7.4) years undergoing primary TKA was performed. Physical, social and leisure activities performed by the patients preoperatively and postoperatively at 3-year were recorded. Activities were selected according to the age, and grouped as passive, moderate and high intensity. The energy spent in each activity was expressed in Metabolic Equivalent of Task (MET) units. Charlson Comorbidity Index, Mini-mental test and Western Ontario and McMaster Universities (WOMAC) scores were also used. Multivariate analysis was used to identify predictors of active patients. RESULTS: Mean WOMAC significantly improved from preoperative (34.8, SD 11.8) to final follow-up (74.4, SD 11.1) (p = 0.001), and the mean energy spent increased from 10.7 (SD 13.6) to 28.2 (SD 16.2) MET-hour weekly (p = 0.001) with a decrease in the passive activities and increase in the moderate activities. However, the participation in high-intensity activities according to age was negligible. Only 65 (61.3%) patients were considered active postoperatively (weekly spending ≥ 40 MET), although the WOMAC scores were not significantly different between active and sedentary patients. Active patients compared with sedentary patients had a significant increase in engagement in physical, social and leisure activities, and a decrease in passive activities. Female gender (p = 0.037), less preoperatively participation in passive activities (p = 0.042), and greater participation in social activities (p = 0.027) were significant predictors of active patients at the final follow-up. CONCLUSION: Overall, most patients increased their activity level postoperatively. However, 38.6% of patients had no increased engagement in moderate physical, social or leisure activities at the medium-term despite improvements in pain and function provided by TKA. LEVEL OF EVIDENCE: II.

FT-Raman Methodology Applied to Study the Effect of Time and Type of Seasoning in the Crafting of Sherry Casks® Used in the Aging of Brandy De Jerez.

Brandy de Jerez is a grape-derived spirit produced in Southern Spain with specific characteristics that come from the casks where it is produced, which must have previously contained some type of Sherry wine for at least 12 months. These casks are known as Sherry Cask®. In this work, Brandies de Jerez aged for different aging times (0, 3, 6 and 12 months) in casks seasoned with three different types of Sherry wines (Fino, Oloroso and Amontillado) have been studied. The samples have been analyzed using FT-Raman spectroscopy, and their chemical characterization has also been realized by studying their total content of organic acid, volatile compounds, and phenolic and furanic compounds. Their chemical study showed that the main differences between the studied samples were due to the duration and the type of seasoning performed. However, the spectra obtained through FT-Raman presented noticeable differences according to cask seasoning time and the Sherry wine used for the process. A PCA (Principal Component Analysis) confirmed that the Brandies de Jerez presented significant differences depending on the seasoning time and type that the casks were subjected to. A PLS-R (Partial Least Squares Regression) study enabled establishing a close correlation between specific regions of the FT-Raman spectra and cask seasoning time.

Analysis of the Localization of Schizosaccharomyces pombe Glucan Synthases in the Presence of the Antifungal Agent Caspofungin.

In recent years, invasive fungal infections have emerged as a common source of infections in immunosuppressed patients. All fungal cells are surrounded by a cell wall that is essential for cell integrity and survival. It prevents cell death and lysis resulting from high internal turgor pressure. Since the cell wall is not present in animal cells, it is an ideal target for selective invasive fungal infection treatments. The antifungal family known as echinocandins, which specifically inhibit the synthesis of the cell wall ß(13)glucan, has been established as an alternative treatment for mycoses. To explore the mechanism of action of these antifungals, we analyzed the cell morphology and glucan synthases localization in Schizosaccharomyces pombe cells during the initial times of growth in the presence of the echinocandin drug caspofungin. S. pombe are rod-shaped cells that grow at the poles and divide by a central division septum. The cell wall and septum are formed by different glucans, which are synthesized by four essential glucan synthases: Bgs1, Bgs3, Bgs4, and Ags1. Thus, S. pombe is not only a perfect model for studying the synthesis of the fungal ß(1-3)glucan, but also it is ideal for examining the mechanisms of action and resistance of cell wall antifungals. Herein, we examined the cells in a drug susceptibility test in the presence of either lethal or sublethal concentrations of caspofungin, finding that exposure to the drug for long periods at high concentrations (>10 µg/mL) induced cell growth arrest and the formation of rounded, swollen, and dead cells, whereas low concentrations (<10 µg/mL) permitted cell growth with a mild effect on cell morphology. Interestingly, short-term treatments with either high or low concentrations of the drug induced effects contrary to those observed in the susceptibility tests. Thus, low drug concentrations induced a cell death phenotype that was not observed at high drug concentrations, which caused transient fungistatic cell growth arrest. After 3 h, high concentrations of the drug caused the following: (i) a decrease in the GFP-Bgs1 fluorescence level; (ii) altered locations of Bgs3, Bgs4, and Ags1; and (iii) a simultaneous accumulation of cells with calcofluor-stained incomplete septa, which at longer times resulted in septation uncoupling from plasma membrane ingression. The incomplete septa revealed with calcofluor were found to be complete when observed via the membrane-associated GFP-Bgs or Ags1-GFP. Finally, we found that the accumulation of incomplete septa depended on Pmk1, the last kinase of the cell wall integrity pathway.

Change in 1-year mortality after hip fracture surgery over the last decade in a European population.

OBJECTIVE: There are scarce data on the mortality after hip fracture surgery for patients treated in the most recent years. The objective of this study was to analyze whether the overall initiatives introduced over the last decade for elderly patients with hip fractures had a positive impact on the 1-year mortality. METHODS: Patients treated during 2010-2012 were compared with patients treated during 2018-2020 for all-cause 1-year mortality. Variables influencing mortality were collected based on the literature, including demographic, comorbidity, cognitive status, and preinjury physical function. Crude mortalities were compared between periods, as well as with the expected mortality in the general population adjusted for age, gender, and year of surgery using the standardized mortality ratio (SMR). A multivariate model was used to identify mortality risk factors. RESULTS: 591 patients older than 65 years were treated during 2010-2012 and 642 patients during 2018-2020. The mean age increased significantly between periods (78.9 vs. 82.6 years, respectively, p = 0.001) in both genders, together with an increase in comorbidity (p = 0.014). The in-hospital mortality risk had no significant difference between periods (2.5 vs. 2.0%, p = 0.339), but the 30-day mortality risk (8.3 vs. 5.5%, p = 0.031) and 1-year mortality risk (16.1 vs. 11.9%, p = 0.023) declined significantly. However, 1-year mortality in 2020 had an excess of 1.33 in SMR. Age older than 80 years, male gender, and Charlson comorbidity index > 2 were significant predictors of 1-year mortality. CONCLUSION: The important evolution achieved in the last decade for the management of patients with hip fracture surgery has led to a significant decline in 1-year mortality, but the 1-year mortality remains significantly higher compared to the general population of similar age and gender.

[Acute appendicitis due to migration of a biliary prosthesis]. / Apendicitis aguda secundaria a obstrucción de orificio apendicular por migración de prótesis biliar.

Acute appendicitis is the most common surgical abdominal pathology worldwide that requires immediate intervention. We report a 78-year-old patient who presented with acute appendicitis. A computed tomography (CT) of the abdomen and pelvis showed acute appendicitis due to appendiceal orifice obstruction from a migrated biliary stent. The condition was successfully treated nonoperatively with endoscopic stent removal, allowing his discharge 72 hours after his admission.

[A successful multidisciplinary approach to a recurrent ischiorectal fossa sarcoma]. / Tratamiento multidisciplinario de un sarcoma recurrente de la fosa isquiorrectal.

Ischiorectal fossa tumors are rare lesions, mostly described in case reports or case series. These lesions represent a diagnostic and therapeutic challenge. Hence, an appropriate preoperative study and multidisciplinary discussion are essential to achieve good oncologic and functional results. We report a case of a 73-year-old male operated on five years before in another health center due to the diagnosis of a left gluteal tumor. The lesion was excised, and biopsies confirmed a high-grade epithelioid sarcoma with a close margin, requiring a subsequent wider excision of the surgical margins. The patient received adjuvant radiotherapy. After four years of follow-up, the patient developed mild pain with skin retraction around the former incision. A local recurrence was diagnosed by imaging. In a multidisciplinary team meeting, a decision to resect the lesion with preservation of the anus and the pelvic floor was taken. The patient underwent a laparoscopic defunctioning loop ileostomy and a resection of the recurrent tumor in the ischiorectal fossa with preservation of the anal sphincter. The defect was covered utilizing a superior gluteal artery perforator flap and a partial gluteus maximus muscle rotation. The tumor was completely excised with negative margins. The patient was discharged without complications after 25 days due to flap management. After one year of follow-up, the patient is recurrence-free, and the ileostomy was closed.

The Effect of Diabetes and Prediabetes on Antituberculosis Treatment Outcomes: A Multicenter Prospective Cohort Study.

BACKGROUND: It is unclear whether diabetes or prediabetes affects unfavorable treatment outcomes and death in people with tuberculosis (PWTB). METHODS: Culture-confirmed, drug-susceptible PWTB, enrolled in the Regional Prospective Observational Research in Tuberculosis (RePORT)-Brazil cohort between 2015 and 2019 (N = 643) were stratified based on glycemic status according to baseline glycated hemoglobin. Unfavorable tuberculosis (TB) outcome was defined as treatment failure or modification, recurrence, or death; favorable outcome was cure or treatment completion. We corroborated the findings using data from PWTB reported to the Brazilian National System of Diseases Notification (SINAN) during 2015-2019 (N = 20 989). Logistic regression models evaluated associations between glycemic status and outcomes. RESULTS: In both cohorts, in univariate analysis, unfavorable outcomes were more frequently associated with smoking, illicit drug use, and human immunodeficiency virus infection. Diabetes, but not prediabetes, was associated with unfavorable outcomes in the RePORT-Brazil (adjusted relative risk [aRR], 2.45; P < .001) and SINAN (aRR, 1.76; P < .001) cohorts. Furthermore, diabetes was associated with high risk of death (during TB treatment) in both RePORT-Brazil (aRR, 2.16; P = .040) and SINAN (aRR, 1.93; P = .001). CONCLUSIONS: Diabetes was associated with an increased risk of unfavorable outcomes and mortality in Brazilian PWTB. Interventions to improve TB treatment outcomes in persons with diabetes are needed.

Quantification of bone marrow edema by MRI of the sacroiliac joints in patients diagnosed with axial spondyloarthritis: results from the ESPeranza cohort.

OBJECTIVE: To evaluate whether the quantification of bone marrow edema (BMO) of the sacroiliac (SI) joints by magnetic resonance imaging (MRI) improves capacity for axial spondyloarthritis (axSpA) classification in comparison with the assessment of sacroiliitis by Assessment of SpondyloArthritis international Society (ASAS) classification criteria. METHOD: This prospective study from the ESPeranza cohort involved 66 subjects with an available MRI of the SI joints at baseline. This subgroup includes patients with axSpA (n = 28), peripheral spondyloarthritis (n = 10), and other diagnoses that were not spondyloarthritis (n = 28). Measures of diagnostic usefulness [area under the curve (AUC), sensitivity, specificity, Youden's J statistic, positive and negative likelihood ratios (LR+ and LR-)] were calculated for MRI of the SI joints according to ASAS criteria and for MRI quantified by means of SCAISS (Spanish tool for semi-automatic quantification of sacroiliac inflammation by MRI in spondyloarthritis). This analysis was stratified in patients who were human leucocyte antigen (HLA)-B27 positive and negative. RESULTS: The AUC value with BMO quantification was 0.919 [95% confidence interval (CI) 0.799-1] for HLA-B27-positive patients and 0.884 (95% CI 0.764-1) for HLA-B27-negative patients. A SCAISS cut-off point of 80 units obtained a specificity of 94.4% and LR+ 7.5, while assessment by ASAS criteria showed a specificity value of 90% and LR+ 6.4. CONCLUSION: For patients with suspected axSpA, quantification of BMO improves the predictive capacity of MRI of the SI joints, for both HLA-B27-positive and HLA-B27-negative patients. Axial spondyloarthritis (axSpA) has a dramatic impact on physical function and quality of life (1). Despite its significant impact, patients with axSpA are normally diagnosed several years after presenting symptoms (2). In this respect, magnetic resonance imaging (MRI) of the sacroiliac (SI) joints has gained significance over the past decade, particularly in the early stages of the disease. Nowadays, imaging tests and human leucocyte antigen (HLA)-B27 testing are among the most important diagnostic procedures for patients with suspected axSpA.