Activity of cefiderocol and innovative ß-lactam/ß-lactamase inhibitor combinations against isogenic strains of Escherichia coli expressing single and double ß-lactamases under high and low permeability conditions.

OBJECTIVES: To analyse the impact of the most clinically relevant ß-lactamases and their interplay with low outer membrane permeability on the activity of cefiderocol, ceftazidime/avibactam, aztreonam/avibactam, cefepime/enmetazobactam, cefepime/taniborbactam, cefepime/zidebactam, imipenem/relebactam, meropenem/vaborbactam, meropenem/xeruborbactam and meropenem/nacubactam against recombinant Escherichia coli strains. METHODS: We constructed 82 E. coli laboratory transformants expressing the main ß-lactamases circulating in Enterobacterales (70 expressing single ß-lactamase and 12 producing double carbapenemase) under high (E. coli TG1) and low (E. coli HB4) permeability conditions. Antimicrobial susceptibility testing was determined by reference broth microdilution. RESULTS: Aztreonam/avibactam, cefepime/zidebactam, cefiderocol, meropenem/xeruborbactam and meropenem/nacubactam were active against all E. coli TG1 transformants. Imipenem/relebactam, meropenem/vaborbactam, cefepime/taniborbactam and cefepime/enmetazobactam were also highly active, but unstable against most of MBL-producing transformants. Combination of ß-lactamases with porin deficiency (E. coli HB4) did not significantly affect the activity of aztreonam/avibactam, cefepime/zidebactam, cefiderocol or meropenem/nacubactam, but limited the effectiveness of the rest of carbapenem- and cefepime-based combinations. Double-carbapenemase production resulted in the loss of activity of most of the compounds tested, an effect particularly evident for those E. coli HB4 transformants in which MBLs were present. CONCLUSIONS: Our findings highlight the promising activity that cefiderocol and new ß-lactam/ß-lactamase inhibitors have against recombinant E. coli strains expressing widespread ß-lactamases, including when these are combined with low permeability or other enzymes. Aztreonam/avibactam, cefiderocol, cefepime/zidebactam and meropenem/nacubactam will help to mitigate to some extent the urgency of new compounds able to resist MBL action, although NDM enzymes represent a growing challenge against which drug development efforts are still needed.

In vitro development of imipenem/relebactam resistance in KPC-producing Klebsiella pneumoniae involves multiple mutations including OmpK36 disruption and KPC modification.

OBJECTIVES: In order to inform and anticipate potential strategies aimed at combating KPC-producing Klebsiella pneumoniae infections, we analysed imipenem/relebactam and ceftazidime/avibactam single-step mutant frequencies, resistance development trajectories, differentially selected resistance mechanisms and their associated fitness cost using four representative high-risk K. pneumoniae clones. METHODS: Mutant frequencies and mutant preventive concentrations were determined using agar plates containing incremental concentrations of ß-lactam/ß-lactamase inhibitor. Resistance dynamics were determined through incubation for 7 days in 10 mL MH tubes containing incremental concentrations of each antibiotic combination up to their 64 × baseline MIC. Two colonies per strain from each experiment were characterized by antimicrobial susceptibility testing, whole genome sequencing and competitive growth assays (to determine in vitro fitness). KPC variants associated with imipenem/relebactam resistance were characterized by cloning and biochemical experiments, atomic models and molecular dynamics simulation studies. RESULTS: Imipenem/relebactam prevented the emergence of single-step resistance mutants at lower concentrations than ceftazidime/avibactam. In three of the four strains evaluated, imipenem/relebactam resistance development emerged more rapidly, and in the ST512/KPC-3 clone reached higher levels compared to baseline MICs than for ceftazidime/avibactam. Lineages evolved in the presence of ceftazidime/avibactam showed KPC substitutions associated with high-level ceftazidime/avibactam resistance, increased imipenem/relebactam susceptibility and low fitness costs. Lineages that evolved in the presence of imipenem/relebactam showed OmpK36 disruption, KPC modifications (S106L, N132S, L167R) and strain-specific substitutions associated with imipenem/relebactam resistance and high fitness costs. Imipenem/relebactam-selected KPC derivatives demonstrated enhanced relebactam resistance through important changes affecting relebactam recognition and positioning. CONCLUSIONS: Our findings anticipate potential resistance mechanisms affecting imipenem/relebactam during treatment of KPC-producing K. pneumoniae infections.

Prenatal Substance Exposure and Neonatal Abstinence Syndrome: State Estimates from the 2016-2020 Transformed Medicaid Statistical Information System.

INTRODUCTION: Estimating Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure rates in Medicaid can help target program efforts to improve access to services. METHODS: The data for this study was extracted from the 2016-2020 Transformed Medicaid Statistical Information System (T-MSIS) Analytic Files (TAF) Research Identifiable Files (RIF) and included infants born between January 1, 2016 and December 31, 2020 with a either a NAS diagnosis or prenatal substance exposure. RESULTS: Between 2016 and 2020, the estimated national rate of NAS experienced a 18% decline, while the estimated national rate of prenatal substance exposure experienced a 3.6% increase. At the state level in 2020, the NAS rate ranged from 3.2 per 1000 births (Hawaii) to 68.0 per 1000 births (West Virginia). Between 2016 and 2020, 28 states experienced a decline in NAS births and 20 states had an increase in NAS rates. In 2020, the lowest prenatal substance exposure rate was observed in New Jersey (9.9 per 1000 births) and the highest in West Virginia (88.1 per 1000 births). Between 2016 and 2020, 38 states experienced an increase in the rate of prenatal substance exposure and 10 states experienced a decline. DISCUSSION: Estimated rate of NAS has declined nationally, but rate of prenatal substance exposure has increased, with considerable state-level variation. The reported increase in prenatal substance exposure in the majority of US states (38) suggest that substances other than opioids are influencing this trend. Medicaid-led initiatives can be used to identify women with substance use and connect them to services.

What is already known about the topic? Neonatal Abstinence Syndrome (NAS) and prenatal substance exposure are significant risk factors for poor neurodevelopmental and mental health outcomes in early childhood. NAS birth rates have been increasing in the US since 2000 and the majority of NAS births are covered by Medicaid.What this article adds? This article estimates national and state-level prenatal substance exposure and NAS rates among Medicaid-covered infants born between 2016-2020 using data from the Transformed Medicaid Statistical Information System. This is the first study using post-2017 data to estimate national NAS rates. The findings can inform future federal and state policy efforts to improve access to screening, diagnosis and treatment among pregnant women with substance use disorder and infants with NAS.

Phenotypic and Molecular Characterization of an Enterobacter ludwigii Clinical Isolate Carrying a Plasmid-Mediated blaIMI-6 Gene.

We report a plasmid-encoded IMI-6 carbapenemase in a clinical isolate of Enterobacter ludwigii from Spain. The isolate belongs to ST641 and was susceptible to expanded-spectrum cephalosporins and resistant to carbapenems. The modified carbapenem inactivation method (mCIM) test was positive, but ß-Carba was negative. Whole-genome sequencing identified the blaIMI-6 gene located in a conjugative IncFIIY plasmid and associated with the LysR-like regulator imiR. Both genes were bracketed by an ISEclI-like insertion sequence and a putatively defective ISEc36 insertion sequence. IMPORTANCE IMI carbapenemases confer an unusual resistance pattern of susceptibility to broad-spectrum cephalosporins and piperacillin-tazobactam but decreased susceptibility to carbapenems, which may make them difficult to detect in routine practice. Commercially available molecular methods for the detection of carbapenemases in clinical laboratories do not usually include blaIMI genes, which could contribute to the hidden dissemination of bacteria producing these enzymes. Techniques should be implemented to detect minor carbapenemases that are not very frequent in our environment and control their dissemination.

Proposals for person-centred care in the COVID-19 era. Delphi study.

BACKGROUND: In this COVID-19 era, we need to rethink the criteria used to measure the results of person-centred care strategies. OBJECTIVE: To identify priorities, and criteria that health services can use to pursue actually the goal of achieving person-centred care. DESIGN: Three-phase online qualitative study performed during May-July of 2020 using the Delphi technique. SETTING AND PARTICIPANTS: An online platform was used for a consensus meeting of 114 participants, including health planning experts, health-care institution managers, clinicians and patients. MAIN OUTCOME MEASURES: Criteria and indicators for the achievement of person-centred care. MAIN RESULTS: The first round began with 125 proposals and 11 dimensions. After the second round, 28 ideas reached a high level of consensus among the participants. Ultimately, the workgroup agreed on 20 criteria for goals in the implementation of person-centred care during the COVID-19 era and 21 related indicators to measure goal achievement. DISCUSSION: Nine dimensions and 28 priorities were identified. These priorities are also in accordance with the quadruple aim approach, which emphasizes the need for care for health-care professionals, without whom it is impossible to achieve a better quality of care. CONCLUSIONS: Person-centred care continues to be a key objective. However, new metrics are needed to ensure its continued development during the restoration of public health services beyond the control of COVID-19. PATIENT OR PUBLIC CONTRIBUTION: Twelve professionals and patient representatives participated voluntarily in the construction of the baseline questionnaire and in the selection of the criteria and indicators using an online platform for consensus meetings.

Necrosis avascular de ambas cabezas femorales en un paciente VIH+ / Avascular necrosis of the femoral heads in a HIV patient

No disponible

Dysexecutive syndrome in amnesic mild cognitive impairment: a multicenter study.

BACKGROUND: Executive functions (EF) in Alzheimer's disease (AD), classically related to the prefrontal cortex, have been forgotten in mild stages, given more importance to temporal lobe associated disorders, such as memory. The study of disexecutive syndrome (DS) has been relegated to advanced stages of the disease. Our goal is to demonstrate that EF are already present in amnesic mild cognitive impairment (aMCI). Furthermore, we are interested in knowing whether poor scores in EF tests are related to the progression to AD or another kind of dementia. METHODS: We studied patients with aMCI (n = 81) and healthy controls (n = 142) from neurological departments of several centers of Basque Country with a cross-sectional design. Patients underwent a complete neuropsychological evaluation, neuroimaging testing APOE genotype and 3 year of prospective follow-up. RESULTS: In the first visit, patients with aMCI showed more alterations in tests that evaluate EF such as Stroop, trail-making and categorical verbal fluency. More alterations were also found in NPI scale (P <0.05). Stroop and Trail-Making test were not associated with the future development of AD, but fluency (p = 0.01) and apathy (p = 0.031) did. No patient developed a different kind of dementia different from AD. CONCLUSIONS: DS is a broad concept not confined to frontal lobes, and can be found in early stages of aMCI. DS impacts negatively on patient autonomy and may have prognostic value.

Estudio con tomografía por emisión de positrones de un caso de demencia vascular por hematoma talámico izquierdo, ejemplo del fenómeno de diasquisis / A study using positron emission tomography of a case of vascular dementia due to left thalamic haematoma, an example of the diaschisis phenomenon

Introducción. Las lesiones vasculares talámicas que se comportan como ictus estratégicos pueden causar amnesia, disfunciones ejecutivas o disfasia, así como síntomas comportamentales o psicológicos, y causar una demencia vascular. Caso clínico. Mujer de 58 años, hipertensa y dislipidémica, que, tras una hemorragia talámica izquierda que evolucionó radiológicamente de manera favorable, presentó un síndrome amnésico grave y otras alteraciones sutiles en la orientación y el lenguaje, dificultades en el manejo del dinero y síntomas depresivos que precisaron tratamiento ansiolítico y antidepresivo, todo lo cual fue causa de limitaciones para el normal desempeño de su trabajo. Seguida en la consulta de neurología, se le practicó una tomografía por emisión de positrones/tomografía axial computarizada con 18F-2-fluoro-2- desoxi-D-glucosa, donde se apreció un hipometabolismo en el tálamo izquierdo y, además, en la región frontal inferior ipsilateral, que se explicaría mediante el fenómeno de diasquisis. Conclusiones. El fenómeno de diasquisis es un hallazgo de neuroimagen y fisiopatológico por el cual los ictus talámicos o de los ganglios basales causan hipoperfusión/hipometabolismo en la corteza ipsilateral o contralateral, y que puede explicar síntomas a distancia corticales. El presente caso evidencia la presencia de conexiones talamocorticales, lo cual ayuda a comprender los circuitos de la memoria y a explicar la asociación en él de otros síntomas corticales, como la disfasia o las alteraciones ejecutivas (AU)

Introduction. Thalamic vascular lesions as strategic strokes can cause amnesia, executive dysfunctions or dysphasia and behavioral or psychological symptoms causing vascular dementia. Case report. A 58 years-old woman with hypertension and dyslipemia, who after a left thalamic hemorrhage with good radiological evolution, presents a severe amnesic syndrome as well as other subtle changes in orientation and in language, difficulties in managing money and depressive symptoms requiring anxiolytic and antidepressive treatment. All this joined to limitations in the normal course of her work. Followed by neurology service, a positron emission tomography with 18F- 2-fluoro-2-deoxy-D-glucose integrated with computed tomography was performed, which showed a hypometabolism in left thalamic area and also in ipsilateral inferior frontal region, explained by the diaschisis phenomenon. Conclusions. Diaschisis phenomenon is a neuroimaging and pathophysiological finding whereby thalamic or basal ganglia strokes cause hypoperfusion/hypometabolism in the ipsilateral or contralateral cortex and could explain cortical distal symptoms. This case report demonstrates the presence of thalamocortical connections, which helps to understand the circuitry of memory and help to explain the association of other cortical symptoms as dysphasia or executive dysfunction (AU)

[A study using positron emission tomography of a case of vascular dementia due to left thalamic haematoma, an example of the diaschisis phenomenon]. / Estudio con tomografia por emision de positrones de un caso de demencia vascular por hematoma talamico izquierdo, ejemplo del fenomeno de diasquisis.

INTRODUCTION: Thalamic vascular lesions as strategic strokes can cause amnesia, executive dysfunctions or dysphasia and behavioral or psychological symptoms causing vascular dementia. CASE REPORT: A 58 years-old woman with hypertension and dyslipemia, who after a left thalamic hemorrhage with good radiological evolution, presents a severe amnesic syndrome as well as other subtle changes in orientation and in language, difficulties in managing money and depressive symptoms requiring anxiolytic and antidepressive treatment. All this joined to limitations in the normal course of her work. Followed by neurology service, a positron emission tomography with 18F-2-fluoro-2-deoxy-D-glucose integrated with computed tomography was performed, which showed a hypometabolism in left thalamic area and also in ipsilateral inferior frontal region, explained by the diaschisis phenomenon. CONCLUSIONS: Diaschisis phenomenon is a neuroimaging and pathophysiological finding whereby thalamic or basal ganglia strokes cause hypoperfusion/hypometabolism in the ipsilateral or contralateral cortex and could explain cortical distal symptoms. This case report demonstrates the presence of thalamocortical connections, which helps to understand the circuitry of memory and help to explain the association of other cortical symptoms as dysphasia or executive dysfunction.

TITLE: Estudio con tomografia por emision de positrones de un caso de demencia vascular por hematoma talamico izquierdo, ejemplo del fenomeno de diasquisis.Introduccion. Las lesiones vasculares talamicas que se comportan como ictus estrategicos pueden causar amnesia, disfunciones ejecutivas o disfasia, asi como sintomas comportamentales o psicologicos, y causar una demencia vascular. Caso clinico. Mujer de 58 años, hipertensa y dislipidemica, que, tras una hemorragia talamica izquierda que evoluciono radiologicamente de manera favorable, presento un sindrome amnesico grave y otras alteraciones sutiles en la orientacion y el lenguaje, dificultades en el manejo del dinero y sintomas depresivos que precisaron tratamiento ansiolitico y antidepresivo, todo lo cual fue causa de limitaciones para el normal desempeño de su trabajo. Seguida en la consulta de neurologia, se le practico una tomografia por emision de positrones/tomografia axial computarizada con 18F-2-fluoro-2-desoxi-D-glucosa, donde se aprecio un hipometabolismo en el talamo izquierdo y, ademas, en la region frontal inferior ipsilateral, que se explicaria mediante el fenomeno de diasquisis. Conclusiones. El fenomeno de diasquisis es un hallazgo de neuroimagen y fisiopatologico por el cual los ictus talamicos o de los ganglios basales causan hipoperfusion/hipometabolismo en la corteza ipsilateral o contralateral, y que puede explicar sintomas a distancia corticales. El presente caso evidencia la presencia de conexiones talamocorticales, lo cual ayuda a comprender los circuitos de la memoria y a explicar la asociacion en el de otros sintomas corticales, como la disfasia o las alteraciones ejecutivas.

Oestrogen receptor polymorphisms are an associated risk factor for mild cognitive impairment and Alzheimer disease in women APOE {varepsilon}4 carriers: a case-control study.

OBJECTIVES: Examine the role of single nucleotide polymorphisms (SNPs) in the oestrogen receptor (ER) genes: rs9340799, rs2234693, rs2228480 (in the ESR1 gene) and rs4986938 (in the ESR2 gene) as a risk factor for amnesic mild cognitive impairment (MCIa) and Alzheimer's disease (AD) and its possible association with the apolipoprotein E (APOE) gene. DESIGN: We have investigated the independent and combined association of different alleles of the oestrogen receptor genes and APOE*ε4 allele with cognitive impairment using a case-control design. SETTING: Participants were prospectively recruited from the neurology departments of several Basque Country hospitals. PARTICIPANTS: This study comprised 816 Caucasian participants who were aged 50 years and older: 204 MCIa, 350 sporadic patients with AD and 262 healthy controls. PRIMARY AND SECONDARY OUTCOME MEASURES: Clinical criteria and neuropsychological tests were used to establish the diagnostic groups (MCIa, AD and healthy controls). A dichotomous variable was used for each allele and genotype and the association with MCIa and AD was established using Logistic Regression Models. RESULTS: Neither alleles nor genotypes of SNPs rs9340799, rs2234693, rs2228480 and rs4986938 of oestrogen receptor genes (ESR1 and ESR2) are independently associated with the risk of MCIa or AD. However, the genetic profile created with the combination of the less represented alleles of these SNPs (expressed as XPAA) was associated with an increased risk for MCIa (OR=3.30, 95% CI 1.28 to 8.54, p=0.014) and AD (OR=5.16, 95% CI 2.19 to 12.14, p<0.001) in women APOE*ε4 allele carriers. CONCLUSIONS: The less represented alleles of SNPs studied are associated with MCIa and AD in APOE*E4 carriers. In particular, the genetic profile created with the less represented alleles of ESR1 and ESR2 SNPs are associated with an increased risk for MCIa and AD in women APOEε4 allele carriers.

The relation between the neutrality index for mitochondrial genes and the distribution of mutational effects on fitness.

We explore factors affecting patterns of polymorphism and divergence (as captured by the neutrality index) at mammalian mitochondrial loci. To do this, we develop a population genetic model that incorporates a fraction of neutral amino acid sites, mutational bias, and a probability distribution of selection coefficients against new nonsynonymous mutations. We confirm, by reanalyzing publicly available datasets, that the mitochondrial cyt-b gene shows a broad range of neutrality indices across mammalian taxa, and explore the biological factors that can explain this observation. We find that observed patterns of differences in the neutrality index, polymorphism, and divergence are not caused by differences in mutational bias. They can, however, be explained by a combination of a small fraction of neutral amino acid sites, weak selection acting on most amino acid mutations, and differences in effective population size among taxa.

(±)-trans,cis-4-Hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one: synthesis and facile dimerization to decahydrodibenzofurans.

An efficient synthesis of (±)-trans,cis-4-hydroxy-5,6-di-O-isopropylidenecyclohex-2-ene-1-one (3) has been developed from acetonide-protected meso-1,2-dihydrocatechol derivative 1 via photooxygenation, then Kornblum-DeLaMare rearrangement. The product is unstable unless its 4-hydroxy group is protected, as it undergoes facile dimerization in solution to a 1:1 mixture of diastereoisomeric decahydrodibenzofurans 8 and 9. A new synthesis of the dihydrocatechol 1 from 1,3-cyclohexadiene has also been developed.

Association of PPARgamma allelic variation, osteoprotegerin and abdominal aortic aneurysm.

OBJECTIVE: We have previously demonstrated high concentrations of the glycoprotein osteoprotegerin (OPG) in biopsies of abdominal aortic aneurysm (AAA), and demonstrated that ligation of the nuclear receptor peroxisome proliferator-activated receptor gamma (PPARgamma) downregulates OPG in vitro and within a mouse model. The aims of this study were to assess the associations between circulating concentrations of OPG, polymorphisms of the gene encoding PPARgamma (PPARG), AAA presence and growth. DESIGN, PATIENTS AND MEASUREMENTS: Two genetic polymorphisms in PPARG were assessed in 4227 men, 699 of whom had an AAA. For 631 men, who had AAAs, maximum aortic diameter was monitored by yearly ultrasound for a median of 5 years. Plasma OPG was measured in 838 men, 318 of whom had an AAA. RESULTS: Plasma concentrations of OPG were independently associated with AAA (adjusted odds ratio 1.38, 95% CI 1.10-1.72). The PPARG c.1347C > T polymorphism was associated with plasma concentrations of OPG (beta 0.12, P < 0.01). The PPARG c.34G > C polymorphism was weakly associated with AAA (adjusted odds ratio 1.28, 95% CI 1.01-1.61). PPARG c.1347C > T was associated with increased AAA growth (recessive model, P = 0.03). CONCLUSIONS: Circulating concentrations of osteoprotegerin are associated with abdominal aortic aneurysm and with one peroxisome proliferator-activated receptor gamma gene polymorphism. Peroxisome proliferator-activated receptor gamma gene polymorphisms are weakly associated with abdominal aortic aneurysm presence and growth. Confirmation of these findings is required in other cohorts.

[Alkaline phosphatase isoenzymes in the serum of patients with renal insufficiency]. / Isoenzimas de fosfatasa alcalina en el suero de pacientes con insuficiencia renal.

OBJECTIVE: The aim of this study was to test the utility of serum alkaline phosphatase isoenzymes determination from patients with renal insufficiency. MATERIAL AND METHODS: Serum levels of alkaline phosphatase isoenzymes were determined in a group of 58 patients: 22 of them suffering acute renal insufficiency (ARI) and 36 with chronic renal failure (CRF) undergoing regular hemodialysis, results obtained were compared from a population of 30 healthy adults. Intestinal, bone, liver, macromolecular and intestinal variant isoenzymes, were separated by electrophoresis on agarose gel and quantified using a densitometer. RESULTS: Were found a significant increase the total alkaline phosphatase activity in both pathologic groups (p < 0.05 in ARI and p < 0.01 in CRF). Isoenzymatic profiles showed: increase of the bone fraction (p < 0.05 in ARI and p < 0.001 in CRF), decrease of the liver isoenzyme (p < 0.001) in both groups, macromolecular fraction elevated in acute patients (p < 0.05) and a significant increase of the intestinal and intestinal variant isoenzyme in the chronic patients (p < 0.001). CONCLUSION: The renal insufficiency modified the normal distribution of alkaline phosphatase isoenzymes and the study of their serum levels could be an effective non-invasive marker, for the evaluation of bone disease and intestinal disorders associated with renal failure.

La psicología como una ciencia de la diversificación de la conciencia / Psychology as a science of the consciousness

En este trabajo realizamos una crítica de la forma institucionalizada de la psicología, con todos los problemas que conlleva el marco estrecho del positivismo en el terreno de la epistemología, la enseñanza, y las consecuencias antropológicas que se derivan de una concepción unilateral y falsamente especializada del saber psicológico. A la luz de un examen crítico de la idea de conciencia como objeto de la psicología en el contexto ontológico amplio de la teoría de la evolución, y devolverle su dignidad en una antropología reformada (AU)