IntroductionSuspected urinary tract infection (UTI) ranks among the most common reasons for antibiotic use in nursing homes. However, diagnosing UTI in this setting is challenging because UTI often presents with non-specific symptomatology. Moreover asymptomatic bacteriuria is common in elderly, which complicates attribution of causality to detection of bacteria in urine. These diagnostic challenges contribute to overuse of antibiotics and emergence of antimicrobial resistance in nursing homes. Given the diagnostic challenges, there is a need for point-of-care (POC) diagnostic tests to support clinical rules for diagnosing UTI. Procalcitonin (PCT) and C reactive protein (CRP) are inflammatory blood markers that have been proven useful to support diagnosis and monitoring of (bacterial) respiratory tract infections and sepsis. While limited studies suggest their usefulness in supporting UTI diagnosis, their utility has not been studied in elderly populations for this purpose.Methods and analysisIn a 24-month matched prospective study, ‘PROGRESS’ will assess and compare the sensitivity of rapid POC measurements of blood CRP and PCT levels to support clinical rules for diagnosing UTI in nursing home residents. The primary outcome measure is sensitivity of the POC tests to identify patients with true UTI based on the predefined definition, as derived from receiver operating curves.Ethics and disseminationThis study will be conducted in accordance with Good Clinical Practice guidelines and the principles of the Declaration of Helsinki. The study protocol is approved by the Medical Ethical Committee of Amsterdam UMC location VUmc with reference number 2017.350 and National Central Committee on Research involving Human Subjects with reference number NL62067.029.17.Trial registration numberNTR6467.

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Background: The importance of protein glycosylation in regulating lipid metabolism is becoming increasingly apparent. We set out to further investigate this by studying patients with type I congenital disorders of glycosylation (CDGs) with defective N-glycosylation. Methods: We studied 29 patients with the 2 most prevalent types of type I CDG, ALG6 (asparagine-linked glycosylation protein 6)–deficiency CDG and PMM2 (phosphomannomutase 2)–deficiency CDG, and 23 first- and second-degree relatives with a heterozygous mutation and measured plasma cholesterol levels. Low-density lipoprotein (LDL) metabolism was studied in 3 cell models—gene silencing in HepG2 cells, patient fibroblasts, and patient hepatocyte-like cells derived from induced pluripotent stem cells—by measuring apolipoprotein B production and secretion, LDL receptor expression and membrane abundance, and LDL particle uptake. Furthermore, SREBP2 (sterol regulatory element-binding protein 2) protein expression and activation and endoplasmic reticulum stress markers were studied. Results: We report hypobetalipoproteinemia (LDL cholesterol [LDL-C] and apolipoprotein B below the fifth percentile) in a large cohort of patients with type I CDG (mean age, 9 years), together with reduced LDL-C and apolipoprotein B in clinically unaffected heterozygous relatives (mean age, 46 years), compared with 2 separate sets of age- and sex-matched control subjects. ALG6 and PMM2 deficiency led to markedly increased LDL uptake as a result of increased cell surface LDL receptor abundance. Mechanistically, this outcome was driven by increased SREBP2 protein expression accompanied by amplified target gene expression, resulting in higher LDL receptor protein levels. Endoplasmic reticulum stress was not found to be a major mediator. Conclusions: Our study establishes N-glycosylation as an important regulator of LDL metabolism. Given that LDL-C was also reduced in a group of clinically unaffected heterozygotes, we propose that increasing LDL receptor–mediated cholesterol clearance by targeting N-glycosylation in the LDL pathway may represent a novel therapeutic strategy to reduce LDL-C and cardiovascular disease.

Background Diagnosing urinary tract infections (UTI) in nursing home residents is complex, as specific urinary symptoms are often absent and asymptomatic bacteriuria (ASB) is prevalent. The aim of this study was to assess the sensitivity of blood C-reactive protein (CRP) and procalcitonin (PCT) measured by Point-of-Care tests (PoCT) to diagnose UTI in this setting. Methods Elderly residents (≥ 65 years old) with a suspected UTI were recruited from psychogeriatric, somatic, or rehabilitation wards, in the thirteen participating nursing homes. CRP and PCT were tested simultaneously in the same study participants. To assess the sensitivities, a stringent definition of ‘true’ UTI was used including the presence of symptoms, urinary leucocytes, positive urine culture and symptom resolution during antibiotic treatment covering isolated uropathogen(s). The original sample size was 440 suspected UTI episodes, to detect a clinically relevant sensitivity of at least 65%, calculated for the matched analysis approach comparing both PoCT. Results After enrolment of 302 episodes (68.6% of the planned sample size) an unplanned and funder-mandated interim analysis was done, resulting in premature discontinuation of the study for futility. For 247 of 266 eligible episodes all mandatory items required for the ‘true’ UTI definition (92.9%) were available. In total, 49 episodes fulfilled our stringent UTI definition (19.8%). The sensitivities of CRP (cut-off 6.5 mg/L) and PCT (cut-off 0.025 ng/mL) were 52.3% (36.7-67.5%, 95%-CI) and 37.0% (23.2-52.5%, 95%-CI) respectively. Conclusion Our results indicate that CRP and PCT are not suitable to distinguish UTI and ASB in nursing home residents. Trial registration Netherlands Trial Registry NL6293