The real world experience of pediatric primary hyperoxaluria patients in the PEDSnet clinical research network.

The rarity of primary hyperoxaluria (PH) challenges our understanding of the disease. The purpose of our study was to describe the course of clinical care in a United States cohort of PH pediatric patients, highlighting health service utilization. We performed a retrospective cohort study of PH patients < 18 years old in the PEDSnet clinical research network from 2009 to 2021. Outcomes queried included diagnostic imaging and testing related to known organ involvement of PH, surgical and medical interventions specific to PH-related renal disease, and select PH-related hospital service utilization. Outcomes were evaluated relative to cohort entrance date (CED), defined as date of first PH-related diagnostic code. Thirty-three patients were identified: 23 with PH type 1; 4 with PH type 2; 6 with PH type 3. Median age at CED was 5.0 years (IQR 1.4, 9.3 years) with the majority being non-Hispanic white (73%) males (70%). Median follow-up between CED and most recent encounter was 5.1 years (IQR 1.2, 6.8). Nephrology and Urology were the most common specialties involved in care, with low utilization of other sub-specialties (12%-36%). Most patients (82%) had diagnostic imaging used to evaluate kidney stones; 11 (33%) had studies of extra-renal involvement. Stone surgery was performed in 15 (46%) patients. Four patients (12%) required dialysis, begun in all prior to CED; four patients required renal or renal/liver transplant.    Conclusion: In this large cohort of U.S. PH children, patients required heavy health care utilization with room for improvement in involving multi-disciplinary specialists. What is Known: • Primary hyperoxaluria (PH) is rare with significant implications on patient health. Typical involvement includes the kidneys; however, extra-renal manifestations occur. • Most large population studies describe clinical manifestations and involve registries. What is New: • We report the clinical journey, particularly related to diagnostic studies, interventions, multispecialty involvement, and hospital utilization, of a large cohort of PH pediatric patients in the PEDSnet clinical research network. • There are missed opportunities, particularly in that of specialty care, that could help in the diagnosis, treatment, and even prevention of known clinical manifestations.

The impact of time-of-day reperfusion on remote ischemic conditioning in ST-elevation myocardial infarction: a RIC-STEMI substudy.

Daytime variation affects the tolerance of cardiomyocytes to ischemia-reperfusion injury (IRI). This study aims to evaluate the impact of time-of-day reperfusion on clinical outcomes of remote ischemic conditioning (RIC) as an adjuvant to primary percutaneous coronary intervention(PPCI) in ST-elevation myocardial infarction(STEMI) patients. A post-hoc analysis of a prospective, single-center parallel 1:1 randomized trial (RIC-STEMI) was performed. This analysis included 448 STEMI patients previously randomized to either PPCI alone (PPCI group) (n = 217) or RIC as an adjuvant to PPCI (RIC + PPCI group) (n = 231). Moreover, the sample was divided according to the time of PPCI: night-morning (22 h-11h59min) (n = 216) or afternoon (12 h-21h59min) (n = 232) groups. The primary follow-up endpoint was a composite of cardiac death and hospitalization due to heart failure. There were no significant differences in the clinical characteristics and the follow-up outcomes between groups. The afternoon period (HR = 0.474; 95% CI 0.230-0.977; p = 0.043) and RIC (HR = 0.423; 95% CI 0.195-0.917; p = 0.029) were independent predictors of the primary follow-up endpoint. An univariate analysis showed a lower frequency of primary follow-up endpoint, just in the afternoon period (10.3%vs0.9%; p = 0.002), in the RIC + PPCI group. A multivariate analysis revealed that RIC was an independent predictor of the primary follow-up endpoint in the afternoon group (HR = 0.098; 95% CI 0.012-0.785; p = 0.029), but not in the night-morning group. In addition, the afternoon period was not an independent predictor of the primary follow-up endpoint when the multivariate analysis was performed in the PPCI group. In conclusion, this study showed an important cardioprotective effect of RIC, namely in the afternoon period, suggesting that the afternoon period enhances the cardioprotection induced by RIC.

Diagnostic Code-Based Screening for Identifying Children with Primary Hyperoxaluria.

PURPOSE: We evaluated the utility of diagnostic codes to screen for patients with primary hyperoxaluria (PH) and evaluate their positive predictive value (PPV) in identifying children with this rare condition in PEDSnet, a clinical research network of pediatric health systems that shares electronic health records data. MATERIALS AND METHODS: We conducted a cross-sectional study of children who received care at 7 PEDSnet institutions from January 2009 through January 2021. We developed and applied screening criteria using diagnostic codes that generated 3 categories of the hypothesized probability of PH. Tier 1 had specific diagnostic codes for PH; tier 2 had codes for hyperoxaluria, oxalate nephropathy, or oxalosis; and tier 3 had a combination of ≥2 codes for disorder of carbohydrate metabolism and ≥1 code for kidney stones. We reviewed the electronic health records of patients with possible PH to confirm PH diagnosis and evaluate the accuracy and timing of diagnostic codes. The PPV of the codes was compared across tiers, time, PH type, and site. RESULTS: We identified 341 patients in the screen; 33 had confirmed PH (9.7%). Tier 1 had the highest proportion of PH; however, the PPV was only 20%. The degree to which an institution accurately represented point of care diagnoses in the data extraction process was predictive of higher PPV. The PPV of diagnostic codes was highest for PH3 (100%) and lowest for PH1 (22.8%). CONCLUSIONS: Diagnostic codes for PH have poor PPV. Findings suggest that one should be careful in research using large databases in which source validation is not possible.

Atrial cardiopathy predicts detection of atrial fibrillation in embolic stroke of undetermined source: real-life data.

OBJECTIVES: Atrial cardiopathy (AC) is more frequent in patients with embolic stroke of undetermined source (ESUS) than in patients with non-cardioembolic stroke. The aim of this work was to describe AC in patients with ESUS and to study its impact on detection of atrial fibrillation (AF) during follow-up. METHODS: This is an observational study of 123 consecutive ESUS patients and 55 ESUS patients from a previous cohort. AC was defined according to the presence of one or more of the following criteria: severe left atrial enlargement, p-wave terminal force in lead V1 > 5000 µVxms, and excessive premature atrial complexes. Unadjusted and adjusted survival analyses for the occurrence of AF and stroke or transient ischemic attack (TIA) were performed. Diagnostic performance of AC for the detection of AF was analyzed. RESULTS: Among 178 patients with ESUS, those with AC (42.7%) were older (p < 0.001), and more frequently had hypertension (p = 0.001) and lower total cholesterol levels (p = 0.001) than patients without AC. The detection of AF during follow-up (median 34 months, interquartile range = 12.8-64) was higher in patients with AC (hazard ratio = 7.00, 95% confidence interval = 2.01-24.39, p = 0.002). This association persisted after adjusting for age, arterial hypertension, and other vascular risk factors. The c-statistic for detection of AF during follow-up for AC was 0.719. There were no differences in stroke or TIA recurrence between groups with and without AC. DISCUSSION: ESUS patients with AC have different baseline clinical characteristics than patients without AC and have a higher detection of AF during follow-up.

Role of the Hydrophobic Bridge in the Carbapenemase Activity of Class D ß-Lactamases.

Class D carbapenemases are enzymes of the utmost clinical importance due to their ability to confer resistance to the last-resort carbapenem antibiotics. We investigated the role of the conserved hydrophobic bridge in the carbapenemase activity of OXA-23, the major carbapenemase of the important pathogen Acinetobacter baumannii We show that substitution of the bridge residue Phe110 affects resistance to meropenem and doripenem and has little effect on MICs of imipenem. The opposite effect was observed upon substitution of the other bridge residue Met221. Complete disruption of the bridge by the F110A/M221A substitution resulted in a significant loss of affinity for doripenem and meropenem and to a lesser extent for imipenem, which is reflected in the reduced MICs of these antibiotics. In the wild-type OXA-23, the pyrrolidine ring of the meropenem tail forms a hydrophobic interaction with Phe110 of the bridge. Similar interactions would ensue with ring-containing doripenem but not with imipenem, which lacks this ring. Our structural studies showed that this interaction with the meropenem tail is missing in the F110A/M221A mutant. These data explain why disruption of the interaction between the enzyme and the carbapenem substrate impacts the affinity and MICs of meropenem and doripenem to a larger degree than those of imipenem. Our structures also show that the bridge directs the acylated carbapenem into a specific tautomeric conformation. However, it is not this conformation but rather the stabilizing interaction between the tail of the antibiotic and the hydrophobic bridge that contributes to the carbapenemase activity of class D ß-lactamases.

Class D ß-lactamases do exist in Gram-positive bacteria.

Production of ß-lactamases of one of four molecular classes (A, B, C and D) is the major mechanism of bacterial resistance to ß-lactams, the largest class of antibiotics, which have saved countless lives since their inception 70 years ago. Although several hundred efficient class D enzymes have been identified in Gram-negative pathogens over the last four decades, none have been reported in Gram-positive bacteria. Here we demonstrate that efficient class D ß-lactamases capable of hydrolyzing a wide array of ß-lactam substrates are widely disseminated in various species of environmental Gram-positive organisms. Class D enzymes of Gram-positive bacteria have a distinct structural architecture and employ a unique substrate-binding mode that is quite different from that of all currently known class A, C and D ß-lactamases. These enzymes thus constitute a previously unknown reservoir of novel antibiotic-resistance enzymes.

Discovery of antibiotic (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one.

In the face of the clinical challenge posed by resistant bacteria, the present needs for novel classes of antibiotics are genuine. In silico docking and screening, followed by chemical synthesis of a library of quinazolinones, led to the discovery of (E)-3-(3-carboxyphenyl)-2-(4-cyanostyryl)quinazolin-4(3H)-one (compound 2) as an antibiotic effective in vivo against methicillin-resistant Staphylococcus aureus (MRSA). This antibiotic impairs cell-wall biosynthesis as documented by functional assays, showing binding of 2 to penicillin-binding protein (PBP) 2a. We document that the antibiotic also inhibits PBP1 of S. aureus, indicating a broad targeting of structurally similar PBPs by this antibiotic. This class of antibiotics holds promise in fighting MRSA infections.

Structure of the extended-spectrum class C ß-lactamase ADC-1 from Acinetobacter baumannii.

ADC-type class C ß-lactamases comprise a large group of enzymes that are encoded by genes located on the chromosome of Acinetobacter baumannii, a causative agent of serious bacterial infections. Overexpression of these enzymes renders A. baumannii resistant to various ß-lactam antibiotics and thus severely compromises the ability to treat infections caused by this deadly pathogen. Here, the high-resolution crystal structure of ADC-1, the first member of this clinically important family of antibiotic-resistant enzymes, is reported. Unlike the narrow-spectrum class C ß-lactamases, ADC-1 is capable of producing resistance to the expanded-spectrum cephalosporins, rendering them inactive against A. baumannii. The extension of the substrate profile of the enzyme is likely to be the result of structural differences in the R2-loop, primarily the deletion of three residues and subsequent rearrangement of the A10a and A10b helices. These structural rearrangements result in the enlargement of the R2 pocket of ADC-1, allowing it to accommodate the bulky R2 substituents of the third-generation cephalosporins, thus enhancing the catalytic efficiency of the enzyme against these clinically important antibiotics.

Discovery of a new class of non-ß-lactam inhibitors of penicillin-binding proteins with Gram-positive antibacterial activity.

Infections caused by hard-to-treat methicillin-resistant Staphylococcus aureus (MRSA) are a serious global public-health concern, as MRSA has become broadly resistant to many classes of antibiotics. We disclose herein the discovery of a new class of non-ß-lactam antibiotics, the oxadiazoles, which inhibit penicillin-binding protein 2a (PBP2a) of MRSA. The oxadiazoles show bactericidal activity against vancomycin- and linezolid-resistant MRSA and other Gram-positive bacterial strains, in vivo efficacy in a mouse model of infection, and have 100% oral bioavailability.

Crystal structure of carbapenemase OXA-58 from Acinetobacter baumannii.

Class D ß-lactamases capable of hydrolyzing last-resort carbapenem antibiotics represent a major challenge for treatment of bacterial infections. Wide dissemination of these enzymes in Acinetobacter baumannii elevated this pathogen to the category of most deadly and difficult to treat. We present here the structure of the OXA-58 ß-lactamase, a major class D carbapenemase of A. baumannii, determined to 1.30-Å resolution. Unlike two other Acinetobacter carbapenemases, OXA23 and OXA-24, the OXA-58 enzyme lacks the characteristic hydrophobic bridge over the active site, despite conservation of the residues which participate in its formation. The active-site residues in OXA-58 are spatially conserved in comparison to those in other class D ß-lactamases. Lys86, which activates water molecules during the acylation and deacylation steps, is fully carboxylated in the OXA-58 structure. In the absence of a substrate, a water molecule is observed in the active site of the enzyme and is positioned in the pocket that is usually occupied by the 6α-hydroxyethyl moiety of carbapenems. A water molecule in this location would efficiently deacylate good substrates, such as the penicillins, but in the case of carbapenems, it would be expelled by the 6α-hydroxyethyl moiety of the antibiotics and a water from the surrounding medium would find its way to the vicinity of the carboxylated Lys86 to perform deacylation. Subtle differences in the position of this water in the acyl-enzyme complexes of class D ß-lactamases could ultimately be responsible for differences in the catalytic efficiencies of these enzymes against last-resort carbapenem antibiotics.

Class D ß-lactamases: are they all carbapenemases?

Carbapenem-hydrolyzing class D ß-lactamases (CHDLs) are enzymes of the utmost clinical importance due to their ability to produce resistance to carbapenems, the antibiotics of last resort for the treatment of various life-threatening infections. The vast majority of these enzymes have been identified in Acinetobacter spp., notably in Acinetobacter baumannii. The OXA-2 and OXA-10 enzymes predominantly occur in Pseudomonas aeruginosa and are currently classified as narrow-spectrum class D ß-lactamases. Here we demonstrate that when OXA-2 and OXA-10 are expressed in Escherichia coli strain JM83, they produce a narrow-spectrum antibiotic resistance pattern. When the enzymes are expressed in A. baumannii ATCC 17978, however, they behave as extended-spectrum ß-lactamases and confer resistance to carbapenem antibiotics. Kinetic studies of OXA-2 and OXA-10 with four carbapenems have demonstrated that their catalytic efficiencies with these antibiotics are in the same range as those of some recognized class D carbapenemases. These results are in disagreement with the classification of the OXA-2 and OXA-10 enzymes as narrow-spectrum ß-lactamases, and they suggest that other class D enzymes that are currently regarded as noncarbapenemases may in fact be CHDLs.

Novel aminoglycoside 2''-phosphotransferase identified in a gram-negative pathogen.

Aminoglycoside 2″-phosphotransferases are the major aminoglycoside-modifying enzymes in clinical isolates of enterococci and staphylococci. We describe a novel aminoglycoside 2″-phosphotransferase from the Gram-negative pathogen Campylobacter jejuni, which shares 78% amino acid sequence identity with the APH(2″)-Ia domain of the bifunctional aminoglycoside-modifying enzyme aminoglycoside (6') acetyltransferase-Ie/aminoglycoside 2″-phosphotransferase-Ia or AAC(6')-Ie/APH(2″)-Ia from Gram-positive cocci, which we called APH(2″)-If. This enzyme confers resistance to the 4,6-disubstituted aminoglycosides kanamycin, tobramycin, dibekacin, gentamicin, and sisomicin, but not to arbekacin, amikacin, isepamicin, or netilmicin, but not to any of the 4,5-disubstituted antibiotics tested. Steady-state kinetic studies demonstrated that GTP, and not ATP, is the preferred cosubstrate for APH(2″)-If. The enzyme phosphorylates the majority of 4,6-disubstituted aminoglycosides with high catalytic efficiencies (k(cat)/K(m) = 10(5) to 10(7) M(-1) s(-1)), while the catalytic efficiencies against the 4,6-disubstituted antibiotics amikacin and isepamicin are 1 to 2 orders of magnitude lower, due mainly to the low apparent affinities of these substrates for the enzyme. Both 4,5-disubstituted antibiotics and the atypical aminoglycoside neamine are not substrates of APH(2″)-If, but are inhibitors. The antibiotic susceptibility and substrate profiles of APH(2″)-If are very similar to those of the APH(2″)-Ia phosphotransferase domain of the bifunctional AAC(6')-Ie/APH(2″)-Ia enzyme.

Triple, simultaneous, very late coronary stent thrombosis.

Coronary artery stent thrombosis is an uncommon but potentially catastrophic complication. The risk of very late stent thrombosis (VLST) raises important safety issues regarding the first generation of drug-eluting stents (DES). Although several complex mechanisms for VLST have been suggested and various predictors have been described, its pathophysiology is not completely understood and it is not known whether longer-term dual antiplatelet therapy reduces the risk. We present a rare case of simultaneous very late DES thrombosis in the three vascular territories, following discontinuation of antiplatelet therapy seven years after stent placement, presenting as cardiogenic shock.

Intelligent Clinical Decision Support System for Managing COPD Patients.

Chronic obstructive pulmonary disease (COPD) is the third leading cause of death worldwide. Health remote monitoring systems (HRMSs) play a crucial role in managing COPD patients by identifying anomalies in their biometric signs and alerting healthcare professionals. By analyzing the relationships between biometric signs and environmental factors, it is possible to develop artificial intelligence models that are capable of inferring patients' future health deterioration risks. In this research work, we review recent works in this area and develop an intelligent clinical decision support system (CIDSS) that is capable of providing early information concerning patient health evolution and risk analysis in order to support the treatment of COPD patients. The present work's CIDSS is composed of two main modules: the vital signs prediction module and the early warning score calculation module, which generate the patient health information and deterioration risks, respectively. Additionally, the CIDSS generates alerts whenever a biometric sign measurement falls outside the allowed range for a patient or in case a basal value changes significantly. Finally, the system was implemented and assessed in a real case and validated in clinical terms through an evaluation survey answered by healthcare professionals involved in the project. In conclusion, the CIDSS proves to be a useful and valuable tool for medical and healthcare professionals, enabling proactive intervention and facilitating adjustments to the medical treatment of patients.

Atrial cardiopathy in young adults with embolic stroke of undetermined source: a myocardial deformation imaging analysis.

BACKGROUND: Atrial cardiopathy (AC) has emerged as a potential pathological thrombogenic atrial substract of embolic stroke of undetermined source (ESUS), even in the absence of atrial fibrillation. Left atrium (LA) myocardial deformation analysis may be of value as a subclinical marker of AC and a predictor of ESUS. AIMS: To compare LA mechanical function between ESUS cases and age and sex-matched controls. METHODS: A single-center analytical study with case-control design was performed. Case group was composed by young patients admitted in the Neurology department from January 2017 to June 2021. Control group was composed by age and sex matched controls recruited from the community. All participants performed echocardiogram and a smaller sample underwent cardiac magnetic resonance. RESULTS: We recruited 31 ESUS patients aged between 18 and 65 years and 31 age and sex matched controls. ESUS patients had a significantly higher prevalence of cardiovascular risk factors and patent foramen ovale (PFO). The prevalence of AC was not different between groups. Echocardiogram parameters, including strain analysis, were similar between groups, except for LA appendage (LAA) ostium variation which was significantly lower in ESUS patients (absolute: 6.5vs8.7mm, p<0.001; relative: 44.5%vs53.4%, p=0.002). After exclusion of patients with PFO, all the results were statistically similar. Regarding cardiac magnetic resonance analysis, there were no statistically significant differences between groups. CONCLUSION: This study shows that in our population atria cardiopathy and atrial function was not associated with ESUS.LAA structural and functional abnormalities may play a major role. The role of LAA in ESUS warrants further studies.

Antibiotic resistance and substrate profiles of the class A carbapenemase KPC-6.

The class A carbapenemase KPC-6 produces resistance to a broad range of ß-lactam antibiotics. This enzyme hydrolyzes penicillins, the monobactam aztreonam, and carbapenems with similar catalytic efficiencies, ranging from 10(5) to 10(6) M(-1) s(-1). The catalytic efficiencies of KPC-6 against cephems vary to a greater extent, ranging from 10(3) M(-1) s(-1) for the cephamycin cefoxitin and the extended-spectrum cephalosporin ceftazidime to 10(5) to 10(6) M(-1) s(-1) for the narrow-spectrum and some of the extended-spectrum cephalosporins.

Class A carbapenemase FPH-1 from Francisella philomiragia.

FPH-1 is a new class A carbapenemase from Francisella philomiragia. It produces high-level resistance to penicillins and the narrow-spectrum cephalosporin cephalothin and hydrolyzes these ß-lactam antibiotics with catalytic efficiencies of 10(6) to 10(7) M(-1) s(-1). When expressed in Escherichia coli, the enzyme confers resistance to clavulanic acid, tazobactam, and sulbactam and has K(i) values of 7.5, 4, and 220 µM, respectively, against these inhibitors. FPH-1 increases the MIC of the monobactam aztreonam 256-fold and the MIC of the broad-spectrum cephalosporin ceftazidime 128-fold, while the MIC of cefoxitin remains unchanged. MICs of the carbapenem antibiotics imipenem, meropenem, doripenem, and ertapenem are elevated 8-, 8-, 16-, and 64-fold, respectively, against an E. coli JM83 strain producing the FPH-1 carbapenemase. The catalytic efficiencies of the enzyme against carbapenems are in the range of 10(4) to 10(5) M(-1) s(-1). FPH-1 is 77% identical to the FTU-1 ß-lactamase from Francisella tularensis and has low amino acid sequence identity with other class A ß-lactamases. Together with FTU-1, FPH-1 constitutes a new branch of the prolific and ever-expanding class A ß-lactamase tree.

The class A ß-lactamase FTU-1 is native to Francisella tularensis.

The class A ß-lactamase FTU-1 produces resistance to penicillins and ceftazidime but not to any other ß-lactam antibiotics tested. FTU-1 hydrolyzes penicillin antibiotics with catalytic efficiencies of 10(5) to 10(6) M(-1) s(-1) and cephalosporins and carbapenems with catalytic efficiencies of 10(2) to 10(3) M(-1) s(-1), but the monobactam aztreonam and the cephamycin cefoxitin are not substrates for the enzyme. FTU-1 shares 21 to 34% amino acid sequence identity with other class A ß-lactamases and harbors two cysteine residues conserved in all class A carbapenemases. FTU-1 is the first weak class A carbapenemase that is native to Francisella tularensis.

[Anomalous origin of the right coronary artery and acute myocardial infarction: cause or coincidence?]. / Origem anómala da coronária direita e enfarte agudo do miocárdio: causa ou coincidência?

Congenital coronary artery anomalies are one of the causes of myocardial ischemia and sudden death in the young, mainly during sports. Origin of the right coronary artery from the left anterior descending artery is very rare, with a prevalence of 0.015%, corresponding to 1.2% of all coronary artery anomalies. The authors present the case of a 22-year-old man, with a history of cocaine use, admitted to hospital with a non-ST elevation acute myocardial infarction. Coronary angiography revealed the presence of this rare coronary anomaly and the absence of atherosclerotic luminal stenosis, and so it was assumed to be a type II infarction caused by cocaine-induced vasospasm of the anomalous vessel.

Generating personalized business card designs from images.

Rising competition in the retail and hospitality sectors, especially in densely populated and touristic destinations is a growing concern for many business owners, who wish to deliver their brand communication strategy to the target audience. Many of these businesses rely on word-of-mouth marketing, delivering business cards to customers. Furthermore, the lack of a dedicated marketing team and budget for brand image consolidation and design creation often limits the brand expansion capability. The purpose of this study is to propose a novel system prototype that can suggest personalized designs for business cards, based on an existing business card picture. Using perspective transformation, text extraction and colour reduction techniques, we were able to obtain features from the original business card image and generate an alternative design, personalized for the end user. We have successfully been able to generate customized business cards for different business types, with textual information and a custom colour palette matching the original submitted image. All of the system modules were demonstrated to have positive results for the test cases and the proposal answered the main research question. Further research and development is required to adapt the current system to other marketing printouts, such as flyers or posters.