Present and future of resistance in Pseudomonas aeruginosa: implications for treatment.

Pseudomonas aeruginosa is a pathogen that has a high propensity to develop antibiotic resistance, and the emergence of multidrug-resistant strains is a major concern for global health. The mortality rate associated with infections caused by this microorganism is significant, especially those caused by multidrug-resistant strains. The antibiotics used to treat these infections include quinolones, aminoglycosides, colistin, and ß-lactams. However, novel combinations of ß-lactams-ß-lactamase inhibitors and cefiderocol offer advantages over other members of their family due to their better activity against certain resistance mechanisms. Selecting the appropriate empiric antibiotic treatment requires consideration of the patient's clinical entity, comorbidities, and risk factors for multidrug-resistant pathogen infections, and local epidemiological data. Optimizing antibiotic pharmacokinetics, controlling the source of infection, and appropriate collection of samples are crucial for successful treatment. In the future, the development of alternative treatments and strategies, such as antimicrobial peptides, new antibiotics, phage therapy, vaccines, and colonization control, holds great promise for the management of P. aeruginosa infections.

[Study of incidence of COVID-19 in Spain and its relationship to geographical province distribution]. / Estudio de la incidencia de COVID-19 en España y su relación geográfica provincial.

BACKGROUND: The aim of this study was to determine incidence of COVID-19 in relationship to geographical distribution among Spain. METHOD: Cluster analysis taking into consideration the incidence of COVID-19 in the provinces and autonomous cities of Spain in each of the first six waves of the pandemic. RESULTS: All the provinces of the Canary Islands, Catalonia and Andalusia form independent clusters. In Comunidad Valenciana, Galicia, País Vasco and Aragón two out of three provinces (three out of four in Galicia) were in the same cluster, with no other provinces. DISCUSSION: The incidence of COVID-19 in Spain in the first six waves forms clusters that reproduce the territorial division of Spain into autonomous communities. Although this could be explained by greater mobility within a community, it cannot be ruled out that this distribution is due to differences in screening, diagnosis, registration or reporting of COVID-19 cases.

Impact of the COVID-19 pandemic on the diagnosis and treatment of onco-hematologic patients: a discussion paper.

We do not know the precise figure for solid organ tumors diagnosed each year in Spain and it is therefore difficult to calculate whether there has been a decrease in cancer diagnoses as a consequence of the pandemic. Some indirect data suggest that the pandemic has worsened the stage at which some non-hematological neoplasms are diagnosed. Despite the lack of robust evidence, oncology patients seem more likely to have a poor outcome when they contract COVID-19. The antibody response to infection in cancer patients will be fundamentally conditioned by the type of neoplasia present, the treatment received and the time of its administration. In patients with hematological malignancies, the incidence of infection is probably similar or lower than in the general population, due to the better protective measures adopted by the patients and their environment. The severity and mortality of COVID-19 in patients with hematologic malignancies is clearly higher than the general population. Since the immune response to vaccination in hematologic patients is generally worse than in comparable populations, alternative methods of prevention must be established in these patients, as well as actions for earlier diagnosis and treatment. Campaigns for the early diagnosis of malignant neoplasms must be urgently resumed, post-COVID manifestations should be monitored, collaboration with patient associations is indisputable and it is urgent to draw the right conclusions to improve our preparedness to fight against possible future catastrophes.

A frequency comb stabilized Ti:Sa laser as a self-reference for ion-trap experiments with a 40Ca+ ion.

In this study, we report on the stabilization of a continuous-wave Ti:Sa laser to an optical frequency comb. The laser is emitting at 866 nm to address one of the transitions required for Doppler cooling of a single 40Ca+ ion in a linear Paul trap (2D3/2 ↔P1/22). The stabilized Ti:Sa laser is utilized to calibrate an ultra-accurate wavelength meter. We certify this self-reference laser source by comparing the results from monitoring the laser-cooled 40Ca+ ion in the linear Paul trap, with those obtained when a HeNe laser is used for calibration. The use of this self-reference is compatible with the simultaneous use of the comb for precision spectroscopy in the same ion-trap experiment.

Treatment of infections caused by carbapenemase-producing Enterobacterales.

Antibiotic resistance is one of the main menaces to public and individual health worldwide. In the last two decades, an increase in the detection of carbapenem-resistant Enterobacterales has been reported. The treatment of infections caused by these strains is a therapeutic challenge. The use of carbapenems may be beneficial depending on MIC value and source of infection. New drugs, with different activity against the different classes of carbapenemases, are developed showing significant benefits.

Implementación del análisis modal de fallos y efectos en una Unidad de Radiofarmacia Hospitalaria / Implementation of the failure modes and effects analysis in a Hospital Radiopharmacy Unit

Objetivo El objetivo de este estudio es la implementación en una Unidad de Radiofarmacia Hospitalaria de una metodología de análisis de riesgos para poder identificar de forma proactiva los posibles modos de fallo y priorizar medidas correctivas. Material y métodos Mediante el análisis modal de fallos y efectos (AMFE) se identificaron los posibles modos de fallo de cada una de las etapas de los procesos de prescripción, preparación y administración de los radiofármacos de diagnóstico y de terapia. A partir de las variables de severidad, probabilidad y detectabilidad se cuantificó el riesgo mediante el número de prioridad de riesgo (NPR) para cada modo de fallo, subproceso y tipo de radiofármaco. Se establecieron medidas de mejora y se calculó la reducción en el NPR. Resultados Se identificaron 96 modos de fallos (58 para los radiofármacos de diagnóstico y 38 para los de terapia). La identificación biunívoca del paciente con el radiofármaco es el modo de fallo con mayor NPR (60) y el subproceso de marcaje celular el que presenta mayor riesgo (NPR 286). Como resultado de las medidas de mejora se disminuyó el NPR global en un 22% para los radiofármacos de diagnóstico y 20% para los de terapia. Esta reducción sería del 46 y el 31%, respectivamente, si se implantara un software de radiofarmacia y tecnología de código de barras en la administración. Conclusiones La aplicación de la metodología AMFE como herramienta de análisis de riesgos permite identificar los puntos críticos de los procesos relacionados con los radiofármacos y priorizar medidas para disminuir el riesgo (AU)

Aim The aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. Materials and methods By means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. Result A total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. Conclusions The application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk (AU)

A systematic literature review and expert consensus on risk factors associated to infection progression in adult patients with respiratory tract or rectal colonisation by carbapenem-resistant Gram-negative bacteria.

OBJECTIVE: Risk factors (RFs) associated with infection progression in patients already colonised by carbapenem-resistant Gram-negative bacteria (CRGNB) have been addressed in few and disperse works. The aim of this study is to identify the relevant RFs associated to infection progression in patients with respiratory tract or rectal colonisation. METHODS: A systematic literature review was developed to identify RFs associated with infection progression in patients with CRGNB respiratory tract or rectal colonisation. Identified RFs were then evaluated and discussed by the expert panel to identify those that are relevant according to the evidence and expert's experience. RESULTS: A total of 8 articles were included for the CRGNB respiratory tract colonisation and 21 for CRGNB rectal colonisation, identifying 19 RFs associated with pneumonia development and 44 RFs associated with infection progression, respectively. After discussion, the experts agreed on 13 RFs to be associated with pneumonia development after respiratory tract CRGNB colonisation and 33 RFs to be associated with infection progression after rectal CRGNB colonisation. Respiratory tract and rectal colonisation, previous stay in the ICU and longer stay in the ICU were classified as relevant RF independently of the pathogen and site of colonisation. Previous exposure to antibiotic therapy or previous carbapenem use were also common relevant RF for patients with CRGNB respiratory tract and rectal colonisation. CONCLUSIONS: The results of this study may contribute to the early identification of CRGNB colonized patients at higher risk of infection development, favouring time-to-effective therapy and improving health outcomes.

Implementation of the failure modes and effects analysis in a Hospital Radiopharmacy Unit.

AIM: The aim of this study is the implementation in a Hospital Radiopharmacy Unit of a risk analysis methodology in order to proactively identify possible failure modes and prioritize corrective measures. MATERIALS AND METHODS: By means of the failure modes and effects analysis (FMEA), the possible failure modes of each of the stages of the processes of prescription, preparation, and administration of radiopharmaceuticals for diagnostic and therapy were identified. From the variables of severity, probability and detectability, the risk was quantified using the Risk Priority Number (RPN) for each failure mode, sub-process, and type of radiopharmaceutical. Improvement measures were established and the reduction in the RPN value was calculated. RESULTS: A total of 96 failure modes were identified (58 for diagnostic radiopharmaceuticals and 38 for therapy). Biunivocal identification of the patient with the radiopharmaceutical is the failure mode with the highest RPN (60) and the radiolabeling cell sub-process the one that has the highest risk (RPN 286). As a result of the improvement measures, the overall RPN was reduced by 22% for diagnostic radiopharmaceuticals and 20% for therapy. This reduction would be 46% and 31% respectively if radiopharmacy software and a barcode technology in the administration were implemented. CONCLUSIONS: The application of the FMEA methodology as a risk analysis tool allows to identify the critical points of the processes related to radiopharmaceuticals and prioritize measures to reduce the risk.

Stereoelectroencephalography in the preoperative assessment of patients with refractory focal epilepsy: experience at an epilepsy centre.

OBJECTIVE: Stereoelectroencephalography (SEEG) is a technique for preoperative evaluation of patients with difficult-to-localise refractory focal epilepsy (DLRFE), enabling the study of deep cortical structures. The procedure, which is increasingly used in international epilepsy centres, has not been fully developed in Spain. We describe our experience with SEEG in the preoperative evaluation of DLRFE. MATERIAL AND METHODS: In the last 8 years, 71 patients with DLRFE were evaluated with SEEG in our epilepsy centre. We prospectively analysed our results in terms of localisation of the epileptogenic zone (EZ), surgical outcomes, and complications associated with the procedure. RESULTS: The median age of the sample was 30 years (range, 4-59 years); 27 patients (38%) were women. Forty-five patients (63.4%) showed no abnormalities on brain MR images. A total of 627 electrodes were implanted (median, 9 electrodes per patient; range, 1-17), and 50% of implantations were multilobar. The EZ was identified in 64 patients (90.1%), and was extratemporal or temporal plus in 66% of the cases. Follow-up was over one year in 55 of the 61 patients undergoing surgery: in the last year of follow-up, 58.2% were seizure-free (Engel Epilepsy Surgery Outcome Scale class I) and 76.4% had good outcomes (Engel I-II). Three patients (4.2%) presented brain haemorrhages. CONCLUSION: SEEG enables localisation of the EZ in patients in whom this was previously impossible, offering better surgical outcomes than other invasive techniques while having a relatively low rate of complications.

Are there differences between ceftolozane/tazobactam and ceftazidime/avibactam in treating patients with complicated abdominal infections? Evidence from clinical trials.

Ceftolozane/tazobactam (C/T) and ceftazidime/avibactam (CZA) are new possibilities of antimicrobial treatment that combined a ß-lactam with a ß-lactamase inhibitor. The United States (US) and European regulatory agencies approved their clinical use in adults with complicated intra-abdominal infections. This study aims to know if one of the two antibiotics obtain better efficacy in adults with complicated intra-abdominal infections and by specific pathogens such as P. aeruginosa or E. coli. A search of all trials in MEDLINE, Scopus, and Web of Science comparing a C/T or CZA based antimicrobial regimen with other treatments in patients with intraabdominal infections until August 2021 was performed. To make indirect comparisons, we used a frequentist approach using the R package netmeta.The effects have been expressed through the relative risk (RR) with its confidence interval. Considering the clinical cure and failure rates between the different trial populations (mMITT, CE, ME) and the mortality at the end of the study, we have not found significant differences between CZA and C/T. In the case of Pseudomonas, the RR of treatment failure between these two antibiotics is 1 (95% CI 0.55-1.18). In the case of E. Coli, although it seems that CZA would have a worse result than C/T, differences did not reach statistical significance (RR1.06; 95% CI 0.9-1.14). In conclusion, we have not found statistically significant differences between ceftolozane-tazobactam and ceftazidime-avibactam in treating cIAI. In regards to E. Coli, our results do not reach significance, but it would be possible that C/T and meropenem had better results than CZA. Perhaps new trials would allow a better profile of the role in different types of patients or infections caused by specific microorganisms in the future.

Respiratory infections in Coronavirus disease 2019.

In the last two years, the capacity of our hospitals has clearly been overwhelmed due to the COVID-19 pandemic The patient who comes to the hospital with a respiratory coinfection does not have the same characteristics as the patient who suffers a superinfection while hospitalized. The number of secondary infections increase proportionally to the severity of the patient's disease. Besides, pathogens that cause a coinfection are clearly differentiated from the pathogens that cause a superinfection. However, in patients subjected to airway manipulation, superinfections by distinct pathogens can occur. Seventy five percent of patients admitted worldwide with COVID-19 (especially during the first two waves of the pandemic) received some form of antibiotic treatment during admission. In this context, it is essential to develop and implement algorithms that allow us to define the predictors in each individual case for the development of a superinfection.

Impacto de la atención farmacéutica en pacientes polimedicados ingresados en un servicio de Geriatría / Impact of pharmaceutical care in polymedicated patients admitted to a geriatric ward

Fundamento. Estimar la prevalencia de prescripción potencialmente inadecuada (PPI) y de problemas relacionados con los medicamentos (PRM) en pacientes ancianos polimedicados hospitalizados, y evaluar el impacto de la intervención farmacéutica sobre dicha prevalencia. Material y métodos. Estudio de intervención, cuasi-experimental, en pacientes polimedicados (≥ 6 fármacos) que ingresaron en un servicio de Geriatría en 2018-2019. Se analizaron las PPI según criterios STOPP/START 2014 y los PRM según el Tercer Consenso de Granada. Los PPI y PRM detectados, junto con posibles acciones para solucionarlos, se remitieron al geriatra responsable. Si al alta el cambio en la prevalencia de PPI y PRM fue ≥75%, se consideró aceptada la intervención. Resultados. Se realizó intervención farmacéutica en 218 pacientes, analizándose 1.837 prescripciones. Al ingreso se observaron PPI (90,8%) y PRM (99,5%). Se realizaron 1.227 intervenciones, el 57,6% sobre PRM. Se aceptó el 53,6% de las intervenciones farmacéuticas; la PPI según criterios STOPP y START se redujo un 49,7 y un 22,1%, respectivamente; los PRM disminuyeron un 60,1%. Las frecuencias y medianas de PRM y de PPI según criterios START y STOPP se redujeron significativamente al alta. Las variables más asociadas con la aceptación de la intervención farmacéutica fueron el geriatra responsable, el número de PPI START y el número de PPI STOPP. Conclusiones. Durante el ingreso hospitalario, la detección de PPI y PRM del tratamiento crónico por el farmacéutico, y en colaboración con el médico del paciente, ayuda a disminuir, la prevalencia de PPI y PRM.(AU)

Background. The aim of the study was estimate the prevalence of potentially inappropriate prescribing (PIP) and drug related problems (DRP) in an acute geriatric ward, and to evaluate the impact of pharmaceutical intervention on their prevalence. Methods. Quasi-experimental, interventional study in polymedicated patients (≥ 6 drugs) who were admitted to a Geriatric ward in 2018-2019. PIP were analyzed according to STOPP/START 2014 criteria and DRP on the Third Consensus of Granada. The PIP and DRP detected, and the possible actions to correct them, PI were sent to the physician in charge. The effect of the intervention was analyzed at hospital discharge; if the change of prevalence of PIP and DRP was ≥75%, the pharmaceutical intervention was considered to be accepted. Results. Pharmaceutical intervention was performed on 218 patients, analyzing 1,837 prescriptions. On admission, PIP (90.8%) and DRP (99.5%) were observed. We carried out 1,227 interventions, 57.6% on DRP. More than half (53.6%) of the pharmaceutical interventions were accepted; the PIP according to the STOPP and START criteria was reduced by 49.7 and 22.1%, respectively; DRP decreased by 60.1%. The frequencies and medians of PRM and PPI according to the START and STOPP criteria decreased significantly at discharge. The variables most frequently associated with acceptance of the pharmaceutical intervention were the geriatrician at charge, the number of PPI START and the number of PPI STOPP. Conclusion. The detection of PIP and DRP of chronic treatment during hospital admission by the pharmacist, and in collaboration with the patient’s doctor, helps to reduce the prevalence of PIP and DRP.(AU)

[Impact of pharmaceutical care in polymedicated patients admitted to a geriatric ward].

BACKGROUND: The aim of the study was estimate the prevalence of potentially inappropriate prescribing (PIP) and drug related problems (DRP) in an acute geriatric ward, and to evaluate the impact of pharmaceutical intervention on their prevalence. METHODS: Quasi-experimental, interventional study in polymedicated patients (= 6 drugs) who were admitted to a Geriatric ward in 2018-2019. PIP were analyzed according to STOPP/START 2014 criteria and DRP on the Third Consensus of Granada. The PIP and DRP detected, and the possible actions to correct them, were sent to the physician in charge. The effect of the intervention was analyzed at hospital discharge; if the change of prevalence of PIP and DRP was =75%, the pharmaceutical intervention was considered to be accepted. RESULTS: Pharmaceutical intervention was performed on 218 patients, analyzing 1,837 prescriptions. On admission, PIP (90.8%) and DRP (99.5%) were observed. We carried out 1,227 interventions, 57.6% on DRP. More than half (53.6%) of the pharmaceutical interventions were accepted; the PIP according to the STOPP and START criteria was reduced by 49.7 and 22.1%, respectively; DRP decreased by 60.1%. The frequencies and medians of PRM and PPI according to the START and STOPP criteria decreased significantly at discharge. The variables most frequently associated with acceptance of the pharmaceutical intervention were the geriatrician at charge, the number of PPI START and the number of PPI STOPP. CONCLUSION: The detection of PIP and DRP of chronic treatment during hospital admission by the pharmacist, and in collaboration with the patient's doctor, helps to reduce the prevalence of PIP and DRP.

Histological and immunohistochemical features suggesting aetiological differences in lymph node and (muco)cutaneous feline tuberculosis lesions.

OBJECTIVES: To identify and describe histological and immunohistochemical criteria that may differentiate between skin and lymph node lesions associated with Mycobacterium (M.) bovis and M. microti in a diagnostic pathology setting. MATERIALS AND METHODS: Archived skin and lymph node biopsies of tuberculous lesions were stained with haematoxylin and eosin, Ziehl-Neelsen and Masson's Trichrome. Immunohistochemistry was performed to detect the expression of calprotectin, CD3 and Pax5. Samples were scored for histological parameters (i.e. granulomas with central necrosis versus small granulomas without central necrosis, percentage necrosis and/or multinucleated giant cells), number of acid-fast bacilli (bacterial index) and lesion percentage of fibrosis and positive immunohistochemical staining. RESULTS: Twenty-two samples were examined (M. bovis n=11, M. microti n=11). When controlling for age, gender and tissue, feline M. bovis-associated lesions more often featured large multi-layered granulomas with central necrosis. Conversely, this presentation was infrequent in feline M. microti-associated lesions, where small granulomas without central necrosis predominated. The presence of an outer fibrous capsule was variable in both groups, as was the bacterial index. There were no differences in intralesional expression of immunohistochemical markers. CLINICAL SIGNIFICANCE: Differences in the histological appearance of skin and lymph node lesions may help to infer feline infection with either M. bovis or M. microti at an earlier stage when investigating these cases, informing clinicians of the potential zoonotic risk. Importantly, cases of tuberculosis can present with numerous acid-fast bacilli. This implies that a high bacterial index does not infer infection with non-zoonotic non-tuberculous mycobacteria.

Diagnostic approach to small-bowel wall thickening: Beyond Crohn's disease and cancer.

Although small-bowel wall thickening is a common manifestation of Crohn's disease and tumors, many other entities can give rise to similar imaging findings. The small bowel is difficult to access by endoscopy, so radiologic imaging tests play an essential role in the diagnosis of conditions involving the small bowel. The main objectives of this paper are to explain the definition of small-bowel wall thickening, analyze the patterns of involvement seen in multidetector computed tomography (MDCT) with intravenous contrast administration, and provide an image-based review of the different causes of small-bowel wall thickening. The differential diagnosis must include many entities because wall thickening can result from immune-mediated, infectious, or vascular causes, as well as from toxicity and other lesser-known entities. As the imaging appearance of many of these conditions overlap, clinical and laboratory findings are necessary to support the imaging diagnosis.

In vitro activity of imipenem/relebactam against Gram-negative clinical isolates in two Spanish tertiary hospitals.

OBJECTIVE: The aim of this study was to analyze the activity of the imipenem-relebactam combination (IMI/REL) against a collection of multidrug-resist Enterobacterales, Pseudomonas aeruginosa and Acinetobacter baumannii clinical isolates. METHODS: The study was conducted in two tertiary hospitals in Spain and included 192 clinical isolates of these 3 genera (139 resistant and 53 susceptible to IMI). The MICs for IMI with and without REL (at a fixed concentration of 4 mg/L) were determined by a standard broth microdilution method according to international recommendations. RESULTS: All IMI-susceptible E. coli strains were also susceptible to IMI/REL. Enterobacterales resistant to IMI due to the production of carbapenemases, the MIC50 and MIC90 decreased from 64/256 with IMI to 8/64 mg/L with IMI/REL. This high activity was principally detected among isolates with KPC enzymes. Enterobacterales with class B carbapenemases, P. aeruginosa carrying VIM carbapenemase and A. baumannii strains showed no changes on IMI MIC50 or MIC90 after adding REL. Among P. aeruginosa strains without carbapenemase the MIC for IMI/REL was reduced between 1 to 5 dilutions. CONCLUSIONS: IMI/REL showed high activity against the strains that carry Klebsiella pneumoniae carbapenemase (KPC) and against carbapenem-resistant P. aeruginosa unrelated to the VIM enzyme, mainly AmpC beta lactamase associated with impermeability. Against strains carrying oxacillinase 48 (OXA-48) associated with extended-spectrum beta-lactamase (ESBL), IMI/REL presented activity only slightly better than IMI and had no beneficial effect superior to IMI against A. baumannii.

Respiratory co-and superinfections in COVID-19.

There are few publications on the impact of coinfection and superinfection in patients with COVID-19. Patients with higher severity are much more prone to secondary bacterial, fungal or viral infections. The overuse of antimicrobials in many viral infections (including SARS-CoV-2 infections) undoubtedly contributes to the current antimicrobial resistance crisis. In the context of COVID-19, we are witnessing an increase in multidrug-resistant bacterial infections in our hospitals. The heterogeneity of published studies makes it critical to perform more large-scale studies to better understand the pathogenesis of coinfections or superinfections in the COVID-19 patient.

The rye transcription factor ScSTOP1 regulates the tolerance to aluminum by activating the ALMT1 transporter.

Plants have evolved different mechanisms to increase their tolerance to aluminum (Al) toxicity and low pH in the soil. The Zn finger transcription factor SENSITIVE TO PROTON RHIZOTOXICITY1 (STOP1) plays an essential role in the adaptation of plants to Al and low pH stresses. In this work, we isolated the ScSTOP1 gene from rye (Secale cereale L.), which is located on chromosome 3RS. The ectopic expression of ScSTOP1 complements the Arabidopsis stop1 mutation in terms of root growth inhibition due to Al and pH stress, as well as phosphate starvation tolerance, suggesting that rye ScSTOP1 is a functional ortholog of AtSTOP1. A putative STOP1 binding motif was identified in the promoter of a well-known STOP1 target from rye and Arabidopsis and was later corroborated by genomic DAP-seq analyses. Coexpression analyses verified that ScSTOP1 activated the promoter of ScALMT1. We have also identified a putative phosphorylatable serine in STOP1 that is phylogenetically conserved and critical for such activation. Our data indicated that ScSTOP1 also regulated Al and pH tolerance in rye.