AbstractObjectiveTo evaluate whether antibiotic prescribing for suspected urinary tract infections in frail older adults can be reduced through a multifaceted antibiotic stewardship ...intervention.DesignPragmatic, parallel, cluster randomised controlled trial, with a five month baseline period and a seven month follow-up period.Setting38 clusters consisting of one or more general practices (n=43) and older adult care organisations (n=43) in Poland, the Netherlands, Norway, and Sweden, from September 2019 to June 2021.Participants1041 frail older adults aged 70 or older (Poland 325, the Netherlands 233, Norway 276, Sweden 207), contributing 411 person years to the follow-up period.InterventionHealthcare professionals received a multifaceted antibiotic stewardship intervention consisting of a decision tool for appropriate antibiotic use, supported by a toolbox with educational materials. A participatory-action-research approach was used for implementation, with sessions for education, evaluation, and local tailoring of the intervention. The control group provided care as usual.Main outcome measuresThe primary outcome was the number of antibiotic prescriptions for suspected urinary tract infections per person year. Secondary outcomes included the incidence of complications, all cause hospital referrals, all cause hospital admissions, all cause mortality within 21 days after suspected urinary tract infections, and all cause mortality.ResultsThe numbers of antibiotic prescriptions for suspected urinary tract infections in the follow-up period were 54 prescriptions in 202 person years (0.27 per person year) in the intervention group and 121 prescriptions in 209 person years (0.58 per person year) in the usual care group. Participants in the intervention group had a lower rate of receiving an antibiotic prescription for a suspected urinary tract infection compared with participants in the usual care group, with a rate ratio of 0.42 (95% confidence interval 0.26 to 0.68). No differences between intervention and control group were observed in the incidence of complications (<0.01 v 0.05 per person year), hospital referrals (<0.01 v 0.05), admissions to hospital (0.01 v 0.05), and mortality (0 v 0.01) within 21 days after suspected urinary tract infections, nor in all cause mortality (0.26 v 0.26).ConclusionsImplementation of a multifaceted antibiotic stewardship intervention safely reduced antibiotic prescribing for suspected urinary tract infections in frail older adults.Trial registrationClinicalTrials.gov NCT03970356.
IntroductionAlmost 60% of antibiotics in frail elderly are prescribed for alleged urinary tract infections (UTIs). A substantial part of this comprises prescriptions in case of non-specific symptoms ...or asymptomatic bacteriuria, for which the latest guidelines promote restrictiveness with antibiotics. We aim to reduce inappropriate antibiotic use for UTIs through an antibiotic stewardship intervention (ASI) that encourages to prescribe according to these guidelines. To develop an effective ASI, we first need a better understanding of the complex decision-making process concerning suspected UTIs in frail elderly. Moreover, the implementation approach requires tailoring to the heterogeneous elderly care setting.Methods and analysisFirst, we conduct a qualitative study to explore factors contributing to antibiotic prescribing for UTIs in frail elderly, using semi-structured interviews with general practitioners, nursing staff, patients and informal caregivers. Next, we perform a pragmatic cluster randomised controlled trial in elderly care organisations. A multifaceted ASI is implemented in the intervention group; the control group receives care as usual. The ASI is centred around a decision tool that promotes restrictive antibiotic use, supported by a toolbox with educational materials. For the implementation, we use a modified participatory-action-research approach, guided by the results of the qualitative study. The primary outcome is the number of antibiotic prescriptions for suspected UTIs. We aim to recruit 34 clusters with in total 680 frail elderly residents ≥70 years. Data collection takes place during a 5-month baseline period and a 7-month follow-up period. Finally, we perform a process evaluation. The study has been delayed for 6 months due to COVID-19 and is expected to end in July 2021.Ethics and disseminationEthical approvals and/or waivers were obtained from the ethical committees in Poland, the Netherlands, Norway and Sweden. The results will be disseminated through publication in peer-reviewed journals and conference presentations.Trial registration number NCT03970356.
To determine the genotype-phenotype association in patients with adenosine deaminase-2 (ADA2) deficiency due to identical homozygous R169Q mutations inCECR1 METHODS: We present a case series of nine ...ADA2-deficient patients with an identical homozygous R169Q mutation. Clinical and diagnostic data were collected and available MRI studies were reviewed. We performed genealogy and haplotype analyses and measured serum ADA2 activity. ADA2 activity values were correlated to clinical symptoms.
Age of presentation differed widely between the nine presented patients (range: 0 months to 8 years). The main clinical manifestations were (hepato)splenomegaly (8/9), skin involvement (8/9) and neurological involvement (8/9, of whom 6 encountered stroke). Considerable variation was seen in type, frequency and intensity of other symptoms, which included aplastic anaemia, acute myeloid leukaemia and cutaneous ulcers. Common laboratory abnormalities included cytopenias and hypogammaglobulinaemia. ADA2 enzyme activity in patients was significantly decreased compared with healthy controls. ADA2 activity levels tended to be lower in patients with stroke compared with patients without stroke. Genealogical studies did not identify a common ancestor; however, based on allele frequency, a North-West European founder effect can be noted. Three patients underwent haematopoietic cell transplantation, after which ADA2 activity was restored and clinical symptoms resolved.
This case series revealed large phenotypic variability in patients with ADA2 deficiency though they were homozygous for the same R169Q mutation inCECR1 Disease modifiers, including epigenetic and environmental factors, thus seem important in determining the phenotype. Furthermore, haematopoietic cell transplantation appears promising for those patients with a severe clinical phenotype.
Abstract
Background
a suspected urinary tract infection (UTI) is the most common reason to prescribe antibiotics in a frail older patient. Frequently, antibiotics are prescribed unnecessarily. To ...increase appropriate antibiotic use for UTIs through antibiotic stewardship interventions, we need to thoroughly understand the factors that contribute to these prescribing decisions.
Objectives
(1) to obtain insight into factors contributing to antibiotic prescribing for suspected UTIs in frail older adults. (2) To develop an overarching model integrating these factors to guide the development of antibiotic stewardship interventions for UTIs in frail older adults.
Methods
we conducted an exploratory qualitative study with 61 semi-structured interviews in older adult care settings in Poland, the Netherlands, Norway and Sweden. We interviewed physicians, nursing staff, patients and informal caregivers.
Results
participants described a chain of decisions by patients, caregivers and/or nursing staff preceding the ultimate decision to prescribe antibiotics by the physician. We identified five themes of influence: (1) the clinical situation and its complexity within the frail older patient, (2) diagnostic factors, such as asymptomatic bacteriuria, (3) knowledge (gaps) and attitude, (4) communication: interprofessional, and with patients and relatives and (5) context and organisation of care, including factors such as availability of antibiotics (over the counter), antibiotic stewardship efforts and factors concerning out-of-hours care.
Conclusions
decision-making on suspected UTIs in frail older adults is a complex, multifactorial process. Due to the diverse international setting and stakeholder variety, we were able to provide a comprehensive overview of factors to guide the development of antibiotic stewardship interventions.
To evaluate the performance in classifying systemic lupus erythematosus by the 2012 Systemic Lupus International Collaborating Clinics criteria (SLICC’12), versus the revised American College of ...Rheumatology criteria from 1997 (ACR’97) in adult and juvenile SLE patients.
A systematic literature search was conducted in PubMed and Embase for studies comparing SLICC’12 and ACR’97 with clinical diagnosis. A meta-analysis was performed to estimate the sensitivity and specificity of SLICC’12 and ACR’97. To assess classification earlier in the disease by either set, sensitivity and specificity were compared for patients with disease duration <5years. Sensitivity and specificity of individual criteria items were also assessed.
In adult SLE (nine studies: 5236 patients, 1313 controls), SLICC’12 has higher sensitivity (94.6% vs. 89.6%) and similar specificity (95.5% vs. 98.1%) compared to ACR’97. For juvenile SLE (four studies: 568 patients, 339 controls), SLICC’12 demonstrates higher sensitivity (99.9% vs. 84.3%) than ACR’97, but much lower specificity (82.0% vs. 94.1%). SLICC’12 classifies juvenile SLE patients earlier in disease course. Individual items contributing to diagnostic accuracy are low complement, anti-ds DNA and acute cutaneous lupus in SLICC’12, and the immunologic and hematologic disorder in ACR’97.
Based on sensitivity and specificity SLICC’12 is best for adult SLE. Following the view that higher specificity, i.e. avoidance of false positives, is preferable, ACR’97 is best for juvenile SLE even if associated with lower sensitivity. Our results on the contribution of the individual items of SLICC’12 and ACR´97 may be of value in future efforts to update classification criteria.
•The 2012 SLICC criteria have the best classification performance for adult SLE.•The 1997 ACR criteria have the best classification performance for juvenile SLE.•The 2012 SLICC criteria classify juvenile patients earlier than the 1997 ACR criteria.
Positive margins dominate clinical outcomes after surgical resections in most solid cancer types, including head and neck squamous cell carcinoma. Unfortunately, surgeons remove cancer in the same ...manner they have for a century with complete dependence on subjective tissue changes to identify cancer in the operating room. To effect change, we hypothesize that EGFR can be targeted for safe and specific real-time localization of cancer.
A dose escalation study of cetuximab conjugated to IRDye800 was performed in patients (n = 12) undergoing surgical resection of squamous cell carcinoma arising in the head and neck. Safety and pharmacokinetic data were obtained out to 30 days after infusion. Multi-instrument fluorescence imaging was performed in the operating room and in surgical pathology.
There were no grade 2 or higher adverse events attributable to cetuximab-IRDye800. Fluorescence imaging with an intraoperative, wide-field device successfully differentiated tumor from normal tissue during resection with an average tumor-to-background ratio of 5.2 in the highest dose range. Optical imaging identified opportunity for more precise identification of tumor during the surgical procedure and during the pathologic analysis of tissues ex vivo. Fluorescence levels positively correlated with EGFR levels.
We demonstrate for the first time that commercially available antibodies can be fluorescently labeled and safely administered to humans to identify cancer with sub-millimeter resolution, which has the potential to improve outcomes in clinical oncology.
Abstract
Background
Evidence linking breast size to breast cancer risk has been inconsistent, and its interpretation is often hampered by confounding factors such as body mass index (BMI). Here, we ...used linkage disequilibrium score regression and two-sample Mendelian randomization (MR) to examine the genetic associations between BMI, breast size and breast cancer risk.
Methods
Summary-level genotype data from 23andMe, Inc (breast size, n = 33 790), the Breast Cancer Association Consortium (breast cancer risk, n = 228 951) and the Genetic Investigation of ANthropometric Traits (BMI, n = 183 507) were used for our analyses. In assessing causal relationships, four complementary MR techniques inverse variance weighted (IVW), weighted median, weighted mode and MR-Egger regression were used to test the robustness of the results.
Results
The genetic correlation (rg) estimated between BMI and breast size was high (rg = 0.50, P = 3.89x10−43). All MR methods provided consistent evidence that higher genetically predicted BMI was associated with larger breast size odds ratio (ORIVW): 2.06 (1.80–2.35), P = 1.38x10−26 and lower overall breast cancer risk ORIVW: 0.81 (0.74–0.89), P = 9.44x10−6. No evidence of a relationship between genetically predicted breast size and breast cancer risk was found except when using the weighted median and weighted mode methods, and only with oestrogen receptor (ER)-negative risk. There was no evidence of reverse causality in any of the analyses conducted (P > 0.050).
Conclusion
Our findings indicate a potential positive causal association between BMI and breast size and a potential negative causal association between BMI and breast cancer risk. We found no clear evidence for a direct relationship between breast size and breast cancer risk.
Anti-EGFR (epidermal growth factor receptor) antibody based treatment strategies have been successfully implemented in head and neck squamous cell carcinoma (HNSCC). Unfortunately, predicting an ...accurate and reliable therapeutic response remains a challenge on a per-patient basis. Although significant efforts have been invested in understanding EGFR-mediated changes in cell signaling related to treatment efficacy, the delivery and histological localization in (peri-)tumoral compartments of antibody-based therapeutics in human tumors is poorly understood nor ever made visible. In this first in-human study of a systemically administered near-infrared (NIR) fluorescently labeled therapeutic antibody, cetuximab-IRDye800CW (2.5 mg/m(2), 25 mg/m(2), and 62.5 mg/m(2)), we show that by optical molecular imaging (i.e. denominated as In vivo Fluorescence Immunohistochemistry) we were able to evaluate localization of fluorescently labeled cetuximab. Clearly, optical molecular imaging with fluorescently labeled antibodies correlating morphological (peri-)tumoral characteristics to levels of antibody delivery, may improve treatment paradigms based on understanding true tumoral antibody delivery.
Objective
Several small case series identified KCTD7 mutations in patients with a rare autosomal recessive disorder designated progressive myoclonic epilepsy (EPM3) and neuronal ceroid lipofuscinosis ...(CLN14). Despite the name KCTD (potassium channel tetramerization domain), KCTD protein family members lack predicted channel domains. We sought to translate insight gained from yeast studies to uncover disease mechanisms associated with deficiencies in KCTD7 of unknown function.
Methods
Novel KCTD7 variants in new and published patients were assessed for disease causality using genetic analyses, cell‐based functional assays of patient fibroblasts and knockout yeast, and electron microscopy of patient samples.
Results
Patients with KCTD7 mutations can exhibit movement disorders or developmental regression before seizure onset, and are distinguished from similar disorders by an earlier age of onset. Although most published KCTD7 patient variants were excluded from a genome sequence database of normal human variations, most newly identified patient variants are present in this database, potentially challenging disease causality. However, genetic analysis and impaired biochemical interactions with cullin 3 support a causal role for patient KCTD7 variants, suggesting deleterious alleles of KCTD7 and other rare disease variants may be underestimated. Both patient‐derived fibroblasts and yeast lacking Whi2 with sequence similarity to KCTD7 have impaired autophagy consistent with brain pathology.
Interpretation
Biallelic KCTD7 mutations define a neurodegenerative disorder with lipofuscin and lipid droplet accumulation but without defining features of neuronal ceroid lipofuscinosis or lysosomal storage disorders. KCTD7 deficiency appears to cause an underlying autophagy‐lysosome defect conserved in yeast, thereby assigning a biological role for KCTD7. Ann Neurol 2018;84:774–788
Abstract
Use of fixed time AI followed by immediate exposure of females to bulls for natural service can be a useful management strategy for commercial cow-calf producers to limit labor and time ...related to bull turnout as well as increase pregnancy rates earlier in the breeding season. Considering potential influence of factors such as bull fertility and time to and length of estrus in females, expectations for outcomes in natural service sire versus AI sire parentage is relatively unknown. We hypothesized that of calves born in the first 14 d of the calving season, less than 5% would be sired by natural service bulls exposed to females immediately following fixed time AI. Heifers (n = 191) and cows (n = 156) were synchronized and inseminated using the 7-d CO-Synch + CIDR fixed time AI protocol. All females were inseminated by the same AI technician using a single sire for heifers and a different single sire for cows. All females were exposed to bulls immediately following insemination. DNA was collected from a random subset of calves (Calves born from heifers n = 59; Calves born from cows n = 89) born in the first 14 d of the calving season for parentage analysis to estimate the overall percentage of calves sired by AI and natural service. Chi-Square tests were used to determine if the percentage of calves actually sired by natural service differed from the hypothesized 5% or less. Among calves born from heifers, the actual percentage sired by natural service (5.1%; n = 3/59) was similar (P = 0.98) to our hypothesized percentage. Among calves born from cows, the actual percentage sired by natural service (14.6%; n = 13/89) was greater (P < 0.001) than our hypothesized percentage of 5%. If commercial producers use fixed time AI followed by immediate bull exposure in cows, natural service bulls may sire more calves early in the calving season than expected.
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