Infant Ustekinumab Clearance, Risk of Infection, and Development After Exposure During Pregnancy.

BACKGROUND: Evidence on ustekinumab safety in pregnancy is gradually expanding, but its clearance in the postnatal period is unknown. The aim of this study was to investigate ustekinumab concentrations in umbilical cord blood and rates of clearance after birth, as well as how these correlate with maternal drug concentrations, risk of infection, and developmental milestones during the first year of life. METHODS: Pregnant women with inflammatory bowel disease were prospectively recruited from 19 hospitals in Denmark and the Netherlands between 2018 and 2022. Infant infections leading to hospitalization/antibiotics and developmental milestones were assessed. Serum ustekinumab concentrations were measured at delivery and specific time points. Nonlinear regression analysis was applied to estimate clearance. RESULTS: In 78 live-born infants from 76 pregnancies, we observed a low risk of adverse pregnancy outcomes and normal developmental milestones. At birth, the median infant-mother ustekinumab ratio was 2.18 (95% confidence interval, 1.69-2.81). Mean time to infant clearance was 6.7 months (95% confidence interval, 6.1-7.3 months). One in 4 infants at 6 months had an extremely low median concentration of 0.015 µg/mL (range 0.005-0.12 µg/mL). No variation in median ustekinumab concentration was noted between infants with (2.8 [range 0.4-6.9] µg/mL) and without (3.1 [range 0.7-11.0] µg/mL) infections during the first year of life (P = .41). CONCLUSIONS: No adverse signals after intrauterine exposure to ustekinumab were observed with respect to pregnancy outcome, infections, or developmental milestones during the first year of life. Infant ustekinumab concentration was not associated with risk of infections. With the ustekinumab clearance profile, live attenuated vaccination from 6 months of age seems of low risk.

Patient-Reported Outcomes and Health-Related Quality of Life in People Living With Ileostomies: A Population-Based, Cross-Sectional Study.

BACKGROUND: The impact of a stoma on long-term health-related quality of life in people living with ileostomies is not clear. OBJECTIVE: This study aimed to describe important patient-reported outcomes and health-related quality of life in people with ileostomies. DESIGN: This is a population-based, cross-sectional study. Patients were invited to answer questionnaires estimating stoma-specific and generic health-related quality of life (EQ-5D-5L and the Major Depression Inventory). Danish norms were retrieved from reference literature. SETTINGS: This study was conducted at the major stoma clinic at Aarhus University Hospital, Denmark. PATIENTS: We invited all patients with ileostomies who were in contact with the clinic between 2012 and 2017. MAIN OUTCOME MEASURES: The primary outcomes measured were patient-reported outcomes specific to people with ileostomies. RESULTS: Of 621 identified patients (50% women), 412 (67%) responded to the survey. Among the responders, 178 (43%) reported that they still had an ileostomy at the time of the survey and were included in the analysis. Fatigue was frequent; 68% (95% CI 60%-75%) reported being tired and 26% (95% CI 20%-33%) answered that they were "always tired," whereas 43% (95% CI 36%-51%) lacked energy, 62% (95% CI 54%-69%) reported poor sleep, and 59% (95% CI 52%-66%) needed to rest during the day. Fifty-six percent (95% CI 48%-63%) needed to know the immediate location of the nearest toilet, and 58% (95% CI 51%-66%) felt sexually unattractive because of their ileostomy. Health-related quality of life measured with generic questions indicated 0.124 points lower health-related quality of life than the Danish norm ( p < 0.001), and 18% (95% CI 13%-25%) scored above the threshold for depression, which is 2.6 times higher than the background population (7%, 95% CI 6%-9%; p < 0.001). LIMITATIONS: This study was limited by potential selection bias, and all participants did not answer all items. CONCLUSIONS: Fatigue and low health-related quality of life is common in people living with ileostomies. Addressing fatigue and stoma-specific challenges in patients with an ileostomy is warranted. See Video Abstract at http://links.lww.com/DCR/B803 . DESENLACES INFORMADOS POR PACIENTES Y CALIDAD DE VIDA RELACIONADA CON LA SALUD EN PERSONAS QUE VIVEN CON ILEOSTOMAS UN ESTUDIO TRANSVERSAL POBLACIONAL: ANTECEDENTES:El impacto de un estoma en la calidad de vida relacionada con la salud a largo plazo en personas que viven con ileostomías no está claro.OBJETIVO:Describir desenlaces importantes informados por pacientes y la calidad de vida relacionada con la salud en personas con ileostomías.DISEÑO:Estudio transversal poblacional. Se invitó a los pacientes a responder cuestionarios que estiman la calidad de vida relacionada con la salud general y específica del estoma (EQ-5D-5L y el Inventario de depresión mayor). Las normas danesas se recopilaron de la literatura de referencia.AJUSTES:El estudio se llevó a cabo en la clínica principal de estomas del Hospital Universitario de Aarhus, Dinamarca.PACIENTES:Invitamos a todos los pacientes con ileostomías que estuvieron en contacto con la clínica entre 2012 y 2017.PRINCIPALES MEDIDAS DE RESULTADO:Resultados informados por el paciente específicos para personas con ileostomías.RESULTADOS:De 621 pacientes identificados (50% mujeres), 412 (66%) respondieron la encuesta. Entre los que respondieron, 178 (43%) informaron que todavía tenían una ileostomía en el momento de la encuesta y fueron incluidos en el análisis. La fatiga era frecuente; el 68% (intervalo de confianza del 95%: 60-75%) informó estar cansado y el 26% (20-33%) respondió "siempre cansado", mientras que el 43% (36-51%) carecía de energía, el 62% (54-69%)) refirieron dormir mal y el 59% (52-6%) necesitaba descansar durante el día. El cincuenta y seis por ciento (48-63%) necesitaba saber la ubicación inmediata del baño más cercano y el 58% (51-66%) se sentía sexualmente poco atractivo debido a su ileostomía. La calidad de vida relacionada con la salud medida con preguntas genéricas indicó una calidad de vida relacionada con la salud 0,124 puntos más baja que la norma danesa ( p < 0,001), y el 18% (13-25%) puntuó con depresión, que es 2.6 veces más alta que la población de base (7%, 6-9%, p < 0,001).LIMITACIONES:Posible sesgo de selección, y no todos los participantes respondieron a todos los ítems.CONCLUSIONES:La fatiga y la baja calidad de vida relacionada con la salud es común en las personas que viven con ileostomías. Se justifica abordar la fatiga y los desafíos específicos del estoma en pacientes con una ileostomía. Consulte Video Resumen en http://links.lww.com/DCR/B803 . (Traducción-Juan Carlos Reyes ).

Early Economic Assessment of Faecal Microbiota Transplantation for Patients with Urinary Tract Infections Caused by Multidrug-Resistant Organisms.

INTRODUCTION: The use of faecal microbiota transplantation (FMT) to eradicate intestinal carriage of multidrug-resistant organisms (MDRO) has been described in case reports and small case series. Although few in numbers, these patients suffer from recurrent infections that may exacerbate both the patients' comorbidities and their healths. In the current study, we hypothesized that FMT for MDRO-related urinary tract infections (UTIs) reduces hospitalisations and associated costs. METHODS: In a cohort of patients referred for FMT from 2015 to 2020, we selected all patients who had consecutively been referred for eradication of MRDO carriage with UTIs. An early economic assessment was performed to calculate hospital-related costs. The overall study cohort was registered at ClinicalTrials, study identifier NCT03712722. RESULTS: We consecutively included five patients with UTIs caused by MDROs. Four of the patients were renal transplant recipients. Patients were followed for median 126 days (range 60-320), where the follow-up duration for each patient was aligned with the number of days from the first UTI to FMT. The median number of UTIs per patient dropped from 4 to 0. Investigating hospital costs, hospital admission days dropped by 87% and monthly hospital costs by 79%. CONCLUSIONS: FMT was effective in reducing the occurrence of UTIs and mediated a marked reduction in hospital costs. We suggest that this strategy is cost-effective. TRIAL REGISTRATION: ClinicalTrials, study identifier NCT03712722.

Donor, patient age and exposure to antibiotics are associated with the outcome of faecal microbiota transplantation for recurrent Clostridioides difficile infection: A prospective cohort study.

BACKGROUND: Faecal microbiota transplantation (FMT) is effective for recurrent Clostridioides difficile infection (rCDI), but its effect varies inexplicably. AIMS: To optimise the effectiveness of FMT for rCDI and validate determinants for effect METHODS: We conducted a cohort study, including all patients treated with FMT for rCDI between October 2018 and June 2020. Statistical process control was used to evaluate the impact of prospective quality improvement on the effect of single FMT treatments per 10-11 patients. Targeting an 80% effect, optimisations included changes to processing procedures, preparation and clinical application of FMT. The primary outcome was the resolution of Clostridioides difficile-associated diarrhoea at week 8. If CDI recurred, FMT was repeated. All patients were followed for 8 weeks after their latest FMT. RESULTS: 183 patients with rCDI received 290 FMT treatments. A single FMT achieved resolution at week 8 in 127 (69%, 95% CI: 62%-76%), while repeated FMT cumulatively achieved resolution in 167/183 (91%, 95% CI: 86%-95%). The single FMT effect varied between 36% and 100% over time. In a mixed-effect model, patient age above 65 years, non-rCDI antibiotics at week 1 post-FMT, and donor were associated with effect. Neither increasing the dosages of faecal microbes nor standardising the processing improved outcomes. CONCLUSION: FMT has a high cumulative effectiveness in patients with rCDI following multiple administrations, but the single FMT effect is variable and may be optimised using statistical process control. Optimising FMT by considering patient age, post-FMT antibiotics, donor and multiple administrations may improve the treatment outcomes. CLINICALTRIALS: gov (Study identifier: NCT03712722).

Health-related quality of life in patients with recurrent Clostridioides difficile infections.

Background: The health-related quality of life (HrQoL) can be substantially affected in patients with recurrent Clostridioides difficile infection (rCDI) but the impact of effective treatment of the infection remains unclear. This study aimed to evaluate the HrQoL in patients with rCDI and estimate the gain in HrQoL associated with effective treatment of rCDI. Methods: Patients' HrQoL was estimated based on EuroQol 5-Dimensions 3-Levels (EQ-5D-3L) questionnaires obtained from a Danish randomised controlled trial (RCT). In the RCT, 64 patients with rCDI were randomised to receive either vancomycin (n = 16), fidaxomicin (n = 24) or faecal microbiota transplantation (FMT) preceded by vancomycin (n = 24). The primary outcome in the RCT was rCDI resolution. Patients were closely monitored during the RCT, and rescue FMT was offered to those who failed their primary treatment. Patients' HrQoL was measured at baseline and at 8- and 26-weeks follow-up. Linear regression analyses conditional on the differences between baseline and follow-up measurements were used to assess statistical significance (p < 0.05). Results: Within 26 weeks of follow-up, 13 (81%) patients treated with vancomycin, 12 (50%) patients treated with fidaxomicin, and 3 (13%) patients treated with FMT had a subsequent recurrence and received a rescue FMT. The average HrQoL for untreated patients with rCDI was 0.675. After receiving effective treatment, this value increased by 0.139 to 0.813 (p < 0.001) at week 8 and by 0.098 to 0.773 (p = 0.003) at week 26 of follow-up compared with baseline. Conclusion: The HrQoL was adversely affected in patients with an active episode of rCDI but increased substantially after receiving an effective treatment algorithm in which rescue FMT was provided in case of a primary treatment failure. Trial registration: The RCT was preregistered at EudraCT (j.no. 2015-003004-24, https://www.clinicaltrialsregister.eu/ctr-search/trial/2015-003004-24/results) and at ClinicalTrials.gov (study identifier NCT02743234, https://clinicaltrials.gov/ct2/show/NCT02743234).

Vedolizumab clearance in neonates, susceptibility to infections and developmental milestones: a prospective multicentre population-based cohort study.

BACKGROUND: Little is known about the consequences of intrauterine exposure to, and the post-natal clearance of, vedolizumab. AIMS: To investigate the levels of vedolizumab in umbilical cord blood of newborns and rates of clearance after birth, as well as how these correlated with maternal drug levels, risk of infection and developmental milestones during the first year of life METHODS: Vedolizumab-treated pregnant women with inflammatory bowel disease were prospectively recruited from 12 hospitals in Denmark and Canada in 2016-2020. Demographics were collected from medical records. Infant developmental milestones were evaluated by the Ages and Stages Questionnaire (ASQ-3). Vedolizumab levels were measured at delivery and, in infants, every third month until clearance. Non-linear regression analysis was applied to estimate clearance. RESULTS: In 50 vedolizumab-exposed pregnancies, we observed 43 (86%) live births, seven (14%) miscarriages, no congenital malformations and low risk of adverse pregnancy outcomes. Median infant:mother vedolizumab ratio at birth was 0.44 (95% confidence interval [CI], 0.32-0.56). The mean time to vedolizumab clearance in infants was 3.8 months (95% CI, 3.1-4.4). No infant had detectable levels of vedolizumab at 6 months of age. Developmental milestones at 12 months were normal or above average. Neither vedolizumab exposure in the third trimester (RR 0.54, 95% CI, 0.28-1.03) nor combination therapy with thiopurines (RR 1.29, 95% CI, 0.60-2.77) seemed to increase the risk of infections in the offspring. CONCLUSIONS: Neonatal vedolizumab clearance following intrauterine exposure is rapid. Infant vedolizumab levels did not correlate with the risk of infections during the first year of life. Continuation of vedolizumab throughout pregnancy is safe.

A standardised model for stool banking for faecal microbiota transplantation: a consensus report from a multidisciplinary UEG working group.

BACKGROUND: Faecal microbiota transplantation is an emerging therapeutic option, particularly for the treatment of recurrent Clostridioides difficile infection. Stool banks that organise recruitment and screening of faeces donors are being embedded within the regulatory frameworks described in the European Union Tissue and Cells Directive and the technical guide to the quality and safety of tissue and cells for human application, published by the European Council. OBJECTIVE: Several European and international consensus statements concerning faecal microbiota transplantation have been issued. While these documents provide overall guidance, we aim to provide a detailed description of all processes that relate to the collection, handling and clinical application of human donor stool in this document. METHODS: Collaborative subgroups of experts on stool banking drafted concepts for all domains pertaining to stool banking. During a working group meeting in the United European Gastroenterology Week 2019 in Barcelona, these concepts were discussed and finalised to be included in our overall guidance document about faecal microbiota transplantation. RESULTS: A guidance document for all domains pertaining to stool banking was created. This document includes standard operating manuals for several processes involved with stool banking, such as handling of donor material, storage and donor screening. CONCLUSION: The implementation of faecal microbiota transplantation by stool banks in concordance with our guidance document will enable quality assurance and guarantee the availability of donor faeces preparations for patients.

Synthesis of proteins by automated flow chemistry.

Ribosomes can produce proteins in minutes and are largely constrained to proteinogenic amino acids. Here, we report highly efficient chemistry matched with an automated fast-flow instrument for the direct manufacturing of peptide chains up to 164 amino acids long over 327 consecutive reactions. The machine is rapid: Peptide chain elongation is complete in hours. We demonstrate the utility of this approach by the chemical synthesis of nine different protein chains that represent enzymes, structural units, and regulatory factors. After purification and folding, the synthetic materials display biophysical and enzymatic properties comparable to the biologically expressed proteins. High-fidelity automated flow chemistry is an alternative for producing single-domain proteins without the ribosome.

A validated GC-MS method for ketamine and norketamine in hair and its use in authentic cases.

This work has shown that it is a valid method for determining ketamine, norketamine and amphetamines derivates in hair samples of forensic cases. This method was validated meeting the criteria of sensitivity and accuracy for detecting repeated consumption of ketamine in hair samples of forensic interest, according to the proposed cut-off for ketamine of 0.5 ng/mg. The detection of norketamine allowed discriminating between active uses and external contamination. The assessed method was applied for analyzing 1189 hair samples of judicial interest received in the INTCF along 15 months, obtaining 62 positive in ketamine consumption. This means a 5.2% of positivity. Ketamine consumers present a profile of young age (21-30 years old), polydrug use with consumption of synthetic substances preferably MDMA and, then, amphetamine. As consumer is collective, prone to consume new psychoactive substances, requires special attention due to they show a consumer profile with higher prevalence in MDMA than amphetamine, indicating that ketamine consumers belong to a subgroup with a different profile within the INTCF casuistry. The results of the exercises of the proficiency tests performed satisfactorily in all cases. In conclusion, it is a suitable method also to evaluate the chronic consumption of ketamine, in addition to amphetamines in the same method of analysis.

Cost savings following faecal microbiota transplantation for recurrent Clostridium difficile infection.

BACKGROUND: Recurrent Clostridium difficile infection (rCDI) is becoming increasingly common. Faecal microbiota transplantation (FMT) is effective for rCDI, but the costs of an FMT and hospital cost savings related to FMT are unknown. The aim of this study was to calculate the cost of an FMT and the total hospital costs before and after FMT. METHODS: This was an observational single-centre study, carried out in a public teaching hospital. We included all patients referred for rCDI from January 2014 through December 2015 and documented costs related to donor screening, laboratory processing, and clinical FMT application. We calculated patient-related hospital costs 1 year before FMT (pre-FMT) and 1 year after FMT (post-FMT). Sensitivity analyses were applied to assess the robustness of the results. RESULTS: We included 50 consecutive adult patients who had a verified diagnosis of rCDI and were referred for FMT. The average cost of an outpatient FMT procedure if donor faeces were applied by colonoscopy was €3,326 per patient and €2,864 if donor faeces were applied using a nasojejunal tube. The total annual pre-FMT hospital costs per patient were €56,415 (95% confidence interval (CI) 41,133-71,697), and these costs dropped by 42% to €32,816 (22,618-42,014) post-FMT (p = 0.004). The main cost driver was hospital admissions. Sensitivity analyses demonstrated cost reductions in all scenarios. CONCLUSIONS: In a public hospital with an implemented FMT service, the average cost of FMT applied by either colonoscopy or nasojejunal tube was €3,095. Total hospital costs dropped by 42% the first year after FMT. The reduction was mainly caused by reductions in the number of hospital admissions and in length of stay.

Man-portable laser-induced breakdown spectroscopy system for in situ characterization of karstic formations.

This paper reports the development and field testing of a man-portable instrument based on laser-induced breakdown spectrometry (LIBS) for inspection and analysis of speleothems. The 50 mJ of a Q-switched Nd:YAG laser operating at 1064 nm was used to generate a plasma on the sample. Plasma emission was then guided using a fiber-optic cable to a 1/10 m spectrometer equipped with a charge-coupled device (CCD) array detector. Plasma light was automatically processed in order to obtain surface and in-depth information from the speleothems. A field campaign in the interior of Nerja Cave (a large karstic formation in the South of Spain) has been carried out, aimed at evaluating the analytical performance of the instrument when operating in an unfriendly environment. Identification analysis of the speleothems' alteration layers and depth profiles of Sr and Ca is carried out and reported.

Faecal microbiota transplantation: establishment of a clinical application framework.

BACKGROUND: Faecal microbiota transplantation (FMT) is currently being established as a second-line treatment for recurrent Clostridium difficile infection. FMT is further being considered for other infectious and inflammatory conditions. Safe and reproducible methods for donor screening, laboratory processing and clinical application of FMT are warranted. METHODS: Here, we describe the development of a complete clinical application framework for FMT. The framework has been developed to comply with the European Tissue Act, thus considering donor faeces for FMT comparable to a human tissue and not a drug. RESULTS: Recruitment and screening of potential faeces donors took place in the public blood donor setting and consisted of questionnaires, blood sampling and faecal sample analysis. Once approved, and following their written informed consent, eligible donors were invited for voluntary faecal donation. Laboratory processing protocols describe the initial handling, cryopreservation and thawing for clinical application. The clinical FMT procedures took place in a gastroenterological setting using a nasojejunal tube or colonoscopy, and follow-ups were performed at 1, 8 and 26 weeks after FMT. Complete traceability of essential equipment, faecal samples and donor-recipient matching data will be maintained and secured for 30 years. CONCLUSION: A clinical FMT service should be consolidated by a complete documentation system that complies with the European Tissue Act. In this paper, we provide a description of such a framework.

Red-legged partridges (Alectoris rufa) as bioindicators for persistent chlorinated chemicals in Spain.

Persistent organochlorine residues such as hexachlorobenzene (HCB), hexachlorocyclohexane isomers (HCHs), chlorocyclodienes, and the DDT group (DDTs) were determined in fat and muscle samples of resident red-legged partridges (Alectoris rufa) hunted in Spain. Chlorinated contamination pattern varied largely depending on geographical distribution. Birds collected from the northern part of Spain contained greater concentrations of lindane (34.4 ng/g fat basis) than those from central or southern Spain. In contrast, red-legged partridges collected in southern locations exhibited elevated levels of p,p-DDE (62.3 ng/g fat basis) as compared with central (31.2 ng/g fat basis) and northern areas (5.6 ng/g fat basis). The only cyclodiene detected, dieldrin, showed higher amounts (3.4 ng/g fat basis) in partridges collected in central Spain. The sex differences in pollutant occurrence and concentrations were negligible. One-year-old birds accumulated greater concentrations of beta-HCH, and dieldrin than older birds. Global comparison of organochlorine concentrations indicated that northern partridges are more contaminated by compounds of industrial origin, whereas southern birds contained greater amounts of agricultural chemicals. Estimates of hazards associated with organochlorine levels in resident red-legged partridges in Spain suggested that southern birds may be at risk from exposure to DDTs, and northern birds may be affected by excessive concentrations of lindane. The use of red-legged partridge as bioindicator for OCP contamination is discussed.