A real or apparent decrease in glomerular filtration rate in patients using olaparib?

PURPOSE: Olaparib is a poly (ADP-ribose) polymerase (PARP) inhibitor indicated for ovarian and metastatic breast cancer. Increased serum creatinine levels have been observed in patients taking olaparib, but the underlying mechanism is unknown. This study aimed to investigate if patients receiving olaparib have increased creatinine levels during olaparib treatment and whether this actually relates to a declined glomerular filtration rate (GFR). METHODS: We retrospectively identified patients using olaparib at the Netherlands Cancer Institute - Antoni van Leeuwenhoek (NKI-AVL) from 2012 until 2020. Patients with at least one plasma or serum sample available at baseline/off treatment and during olaparib treatment were included. Cystatin C levels were measured, creatinine levels were available and renal function was determined by calculating the estimated glomerular filtration rate (eGFR) using the Creatinine Equation (CKD-EPI 2009) and the Cystatin C Equation (CKD-EPI 2012). RESULTS: In total, 66 patients were included. Olaparib treatment was associated with a 14% increase in median creatinine from 72 (inter quartile range (IQR): 22) µmol/L before/off treatment to 82 (IQR: 20) µmol/L during treatment (p < 0.001) and a 13% decrease in median creatinine-derived eGFR from 86 (IQR: 26) mL/min/1.73 m2 before/off treatment to 75 (IQR: 29) mL/min/1.73 m2 during treatment (p < 0.001). Olaparib treatment had no significant effect on median cystatin C levels (p = 0.520) and the median cystatin C-derived eGFR (p = 0.918). CONCLUSIONS: This study demonstrates that olaparib likely causes inhibition of renal transporters leading to a reversible and dose-dependent increase in creatinine and does not affect GFR, since the median cystatin C-derived eGFR was comparable before/off treatment and during treatment of olaparib. Using the creatinine-derived eGFR can give an underestimation of GFR in patients taking olaparib. Therefore, an alternative renal marker such as cystatin C should be used to accurately calculate eGFR in patients taking olaparib.

C-reactive protein kinetics and its predictive value in orthopedic (trauma) surgery: A systematic review.

In Orthopedic Trauma Surgery (OTS), C-reactive- protein (CRP) is a widely used marker for the diagnosis of postoperative wound infections (POWI's) and other complications. The aim of this systematic review was to describe specific CRP kinetics and to evaluate the diagnostic value of CRP for te detection of post-operative complications in OTS. The same pattern is reported consistently, where the highest levels of CRP are found at post-operative-day two or three, returning to normal in three weeks. Amplitude varies per procedure. Persistently high CRP levels or secondary increases may indicate complications. A low CRP may be used to rule out complications.

Variation in the CTLA4 3'UTR has phenotypic consequences for autoreactive T cells and associates with genetic risk for type 1 diabetes.

Cytotoxic T-lymphocyte-associated protein 4 (CTLA4) is a protein receptor that downregulates the immune system. CTLA4 gene variants associate with various autoimmune diseases, including type 1 diabetes. Fine mapping of the genetic risk has shown that the genomic region near CTLA4 marked by the single-nucleotide polymorphism (SNP) CT60A/G (rs3087243) acts as a susceptibility factor. Yet, the functional basis for the increased susceptibility conferred by rs3087243 remains unclear. We demonstrate that the length of the dinucleotide (AT)n repeat within the CTLA4 3' untranslated region (3'UTR) strongly associates with the risk of SNP CT60A/G (P<6.5 × 10(-72)). Genomic (AT)n repeat length inversely correlated with CTLA4 messenger RNA (mRNA) and protein levels in islet autoreactive T-cell lines. Transfer of a long (AT)n element into T cells lead to a reduction of mRNA compared to a short (AT)n element. Thus, this study provides evidence for a role of the CTLA4 3'UTR (AT)n repeat in the increased genetic risk for islet autoimmunity associated with the CTLA4 locus.

Survival of autoreactive T lymphocytes by microRNA-mediated regulation of apoptosis through TRAIL and Fas in type 1 diabetes.

Autoreactive CD8(+) T cells recognizing autoantigens expressed by pancreatic islets lead to the destruction of insulin-producing beta cells in type 1 diabetes (T1D), but these T cells also occur in healthy subjects. We tested the hypothesis that uncontrolled expansion of diabetogenic T cells in patients occurs, resulting from failure to activate apoptosis. We compared function, transcriptome and epigenetic regulation thereof in relation with fate upon repeated exposure to islet-autoantigen of islet autoreactive T cells from healthy and type 1 diabetic donors with identical islet epitope specificity and HLA-A2 restriction. Patient's T cells proliferated exponentially, whereas those of non-diabetic origin succumbed to cell death. Transcriptome analysis revealed reduced expression of TRAIL, TRAIL-R2, FAS and FASLG (members of the extrinsic apoptosis pathway) in patient-derived compared with healthy donor-derived T cells. This was mirrored by increased expression of microRNAs predicted to regulate these particular genes, namely miR-98, miR-23b and miR-590-5p. Gene-specific targeting by these microRNAs was confirmed using dual-luciferase reporter assays. Finally, transfection of these microRNAs into primary T cells reduced FAS and TRAIL mRNA underscoring their functional relevance. We propose that repression of pro-apoptotic pathways by microRNAs contributes to unrestricted expansion of diabetogenic cytotoxic T cells, implicating microRNA-mediated gene silencing in islet autoimmunity in T1D.

Post-transcriptional control of candidate risk genes for type 1 diabetes by rare genetic variants.

The genetic variation causal for predisposition to type 1 diabetes (T1D) remains unidentified for the majority of known T1D risk loci. MicroRNAs function as post-transcriptional gene regulators by targeting microRNA-binding sites in the 3' untranslated regions (UTR) of mRNA. Genetic variation within the 3'-UTR of T1D-associated genes may contribute to T1D development by altering microRNA-mediated gene regulation. In silico analysis of variable sites predicted altered microRNA binding in established T1D loci. Functional implications were assessed for variable sites in the 3'-UTR of T1D candidate risk genes CTLA4 and IL10, both involved in immune regulation. We confirmed that in these genes 3'-UTR variation either disrupted or introduced a microRNA-binding site, affecting the repressive capacity of miR-302a* and miR-523, respectively. Our study points to the potential of 3'-UTR variation to affect T1D pathogenesis by altering post-transcriptional gene regulation by microRNAs.

Indwelling time of peripherally inserted central catheters and incidence of bloodstream infections in haematology patients: a cohort study.

BACKGROUND: We aimed to assess whether longer indwelling time of peripherally inserted central catheters (PICC) increases risk of central line associated bloodstream infections (CLABSI) in haematology patients. METHODS: Multicentre retrospective cohort study among haematology patients receiving PICCs between 2013 and 2015. Occurrence of CLABSI based on CDC definitions was assessed. We calculated incidence rates, determined risk factors for CLABSI and used Poisson regression models to assess the risk of developing CLABSI as a function of PICC dwell time. We compared diagnoses and treatment characteristics between 2013-2015 and 2015-2020. RESULTS: 455 PICCs placed in 370 patients were included, comprising 19,063 catheter days. Median indwelling time was 26 days (range 0-385) and CLABSI incidence was 4.0 per 1000 catheter days, with a median time to CLABSI of 33 days (range 18-158). Aplastic anaemia (AA) was associated with an increased risk of CLABSI; patients undergoing autologous stem cell transplantation (SCT) were less likely to develop CLABSI. In the unadjusted analysis, PICCs with an indwelling time of 15-28 days, 29-42 days, 43-56 days and > 56 days each had an increased CLABSI incidence rate ratio of 2.4 (1.2-4.8), 2.2 (0.95-5.0), 3.4 (1.6-7.5) and 1.7 (0.9-3.5), respectively, compared to PICCs in place for < 15 days. However, after adjusting for AA and SCT, there was no significant difference in incidence rates between dwell times (p 0.067). CONCLUSIONS: Our study shows that risk of CLABSI does not appear to increase with longer PICC indwelling time. Routine replacement of PICCs therefore is unlikely to prevent CLABSI in this population.

[Dutch guideline on necrotizing soft tissue infections]. / Richtlijn 'Necrotiserende wekedeleninfecties'.

In 2018 the first Dutch guideline on necrotizing soft tissue infections (NSTIs) was drafted. Its aim is to standardize the care of this disease in order to reduce variation, and thereby improve the quality of care. This guideline is a benchmark for all healthcare providers who deal with this devastating disease; it focuses on diagnostics, treatment options and organization of care. Given the low incidence, the complexity and the fulminant course of NSTIs, it is important to ensure continuous specialized care. Therefore it is recommended to make regional agreements about referral to specialized centres. Surgical exploration remains the gold standard for diagnosis. The empirical antibiotic regimen depends on if the onset of disease is community or nosocomial, and if its aetiology is a monomicrobial (type I) or a polymicrobial (type II). The guideline recommends that intravenous immunoglobulin (IVIg) therapy be started if gram staining reveals streptococci. IVIg must be discontinued if group-A streptococcus is excluded as a causative agent.

Early detection of severe injuries after major trauma by immediate total-body CT scouts.

INTRODUCTION: Evaluation of immediate total-body CT (iTBCT) scouts during primary trauma care could be clinically relevant for early detection and treatment of specific major injuries. The aim of this study was to determine the diagnostic usefulness of TBCT scouts in detecting life-threatening chest and pelvic injuries. METHODS: All patients who underwent an iTBCT during their primary trauma assessment in one trauma center between April 2011 and November 2014 were retrospectively included. Two experienced trauma surgeons and two emergency radiologists evaluated iTBCT scouts with structured questionnaires. Inter-observer agreement and diagnostic properties were calculated for endotracheal tube position and identification of pneumo- and/or hemothorax and pelvic fractures. Diagnostic properties of iTBCT scouts for indication for chest tube placement and pelvic binder application were calculated in comparison to decision based on iTBCT. RESULTS: In total 220 patients with a median age of 37 years (IQR 26-59) were selected with a median Injury Severity Score of 18 (IQR 9-27). There was moderate to substantial inter-observer agreement and low false positive rates for pneumo- and/or hemothorax and for severe pelvic fractures by iTBCT scouts. For 19.8%-22.5% of the endotracheal intubated patients trauma surgeons stated that repositioning of the tube was indicated. Positive predictive value and sensitivity were respectively 100% (95%CI 52%-100%) and 50% (95%CI 22%-78%) for decisions on chest tube placement by trauma surgeon 1 and 67% (95%CI 13%-98%) and 22% (95%CI 4%-60%) for decisions by trauma surgeon 2. Only in one of 14 patients the pelvic binder was applied after iTBCT acquisition. CONCLUSIONS: iTBCT scouts can be useful for early detection of pneumo- and/or hemothorax and severe pelvic fractures. Decision for chest tube placement based on iTBCT scouts alone is not recommended.

[Diagnosis and treatment of fracture-related infections]. / Diagnostiek en behandeling van fractuur-gerelateerde infecties.

Fracture-related infection (FRI) is a serious complication after fracture care and can lead to severe morbidity with loss of quality of life, a significant increase in medical expenses and loss of participation in work and social life. Early recognition, adequate surgical debridement, deep uncontaminated tissue cultures with (if indicated) soft tissue reconstruction and fracture stabilization followed by antibiotic therapy are the cornerstones of the successful management of FRI. Recently, in 2018, the AO/EBJIS consensus definition for FRI was published and both national and international working groups are being assembled and provide guidelines and tools for the care of patients with FRI. This paper is a synopsis of the Dutch guideline on FRI (2018), illustrated by a clinical case, and is aiming to provide an overview of the current knowledge on diagnosis and treatment of this disease.

[Splenectomy in a large general hospital: often caused by iatrogenic injury, often causing multiple complications; poor adherence to post-operative guidelines for vaccination and prophylaxis]. / Splenectomie in een groot algemeen ziekenhuis: vaak iatrogeen letsel als oorzaak, veel complicaties tot gevolg; naleving postoperatieve richtlijnen voor vaccinatie en profylaxe gebrekkig.

OBJECTIVE: To assess the indications, complications and mortality associated with splenectomy in a large general hospital, and to evaluate adherence to guidelines for postoperative vaccination and prophylactic antibiotics. DESIGN: Retrospective, descriptive. METHOD: Data were collected on 106 patients who underwent splenectomy between 1999 and 2004. Indications for surgery, complications, duration of hospitalisation, and vaccination status were investigated retrospectively. Patients were contacted by telephone for a structured interview regarding vaccination and antibiotic prophylaxis. RESULTS: Of the 95 patients with sufficient data for analysis, 41 underwent elective surgery and 54 underwent non-elective surgery, including 37 who required splenectomy due to iatrogenic injury. Posteroperative complications arose in 45 patients, including 23 who developed serious complications. 10 patients died due to complications, including 7 who died within one month after the procedure. Vaccination coverage for the entire group was 58%. CONCLUSION: In this large general hospital, splenectomy was often performed due to iatrogenic injury and was associated with a relatively high complication rate. Adherence to guidelines on vaccination and prophylactic antibiotics could be improved.

[Multidisciplinary approach of facial injuries]. / Multidisciplinaire aanpak bij aangezichtsletsel.

BACKGROUND: Approximately one quarter of polytrauma patients has facial injuries, which usually lead to loss of form and function. Several specialties are involved in the acute and reconstructive phases of facial injuries, such as oral and maxillofacial surgery, otorhinolaryngology, plastic surgery, ophthalmology and dentistry. CASE DESCRIPTION: A 25-year-old man with severe facial injuries was brought to the shock room after sustaining high-energy trauma. He had a panfacial fracture that required reconstruction. This was done with two surgeries, with an interval of 4 days. The patient recovered successfully after this. CONCLUSION: Because of the complexity of facial trauma, many factors are involved in acute care and treatment. It is therefore important to designate one coordinating specialty to guide this process. The oral and maxillofacial surgeon plays a vital role in this.

[Diagnostic image (263). A soccer playing girl with a painful hip]. / Diagnose in beeld (263). Een voetballend meisje met pijn in de heup.

In a 13-year-old girl sudden pain in the right hip after playing soccer was caused by anterior inferior iliac spine avulsion.

[The pitfalls of necrotising soft tissue infection: a 'wake-up call' for surgeons]. / De valkuilen bij necrotiserende wekedeleninfecties.

Necrotising soft tissue infections require early consultation of an experienced surgeon, regardless of what time of day they occur. Delays in diagnosis and treatment should not occur. Necrotectomy should be skin-sparing when possible. A low threshold for consultation with a tertiary referral center is recommended.

Immunohistochemical analysis of iris biopsy specimens from patients with Fuchs' heterochromic cyclitis.

Using immunohistochemical techniques, we analyzed iris biopsy specimens from eight patients with Fuchs' heterochromic cyclitis, seven patients with various other types of uveitis, and eight glaucoma patients without uveitis. No specific abnormalities related to Fuchs' heterochromic cyclitis could be detected. Four of the patients with Fuchs' heterochromic cyclitis and four of the patients with uveitis showed evidence of an inflammatory cell infiltrate, which was a mixture of interleukin-2 receptor-negative T helper and suppressor cells, B lymphocytes, and plasma cells. Only an occasional T lymphocyte could be seen in two of the patients without uveitis. The class II antigen HLA-DR was expressed on iris stromal cells in every patient in the Fuchs' heterochromic cyclitis group and uveitis group and in six of the patients in the nonuveitis group. In six of the Fuchs' heterochromic cyclitis patients, including two without immunohistochemical evidence of inflammatory cell infiltrate, histologic abnormalities were present on hematoxylin and eosin sections.

[Diagnostic image (212). A man with severe abdominal pain]. / Diagnose in beeld (212). Een man met heftige buikpijn.

A 36-year-old man presented with acute abdominal pain due to occlusion of the superior mesenteric artery associated with intestinal rotation caused by an upper abdominal postoperative adhesion.

[Diagnostic image (193). A man with a palpable mass in the upper abdomen. Porcelain gallbladder]. / Diagnose in beeld (193). Een man met een palpabele zwelling in de bovenbuik. Porseleinen galblaas.

In a 73-year-old man with a non-tender palpable mass in the right part of the upper abdomen and soft stool a porcelain gallbladder was observed at radiological examination.

Complete medial column dislocation at the cuneonavicular joint: an unusual Lisfranc-like injury.

Lisfranc injuries represent a wide spectrum of different injuries at the tarsometatarsal joint. Not all types fit the currently available classifications. This case illustrates a rare subtype of a Lisfranc injury, with a dislocation of the entire first ray. It is presented to create more awareness for midfoot injuries. This article reviews the literature and provides recommendations for the treatment of similar cases in the future.

Aerosol delivery from spacers in wheezy infants: a daily life study.

The aims of this study were to assess and compare dose delivery and dose variability of pressurized metered dose inhalers (pMDI)/spacers in wheezy infants in daily life and to investigate factors influencing aerosol delivery. In an open randomized crossover study in 25 wheezy infants aged 5-26 months, a metal spacer (Nebuchamber), a detergent coated (DC) and a non-detergent coated (nonDC) plastic spacer (Babyhaler) were tested at home for 7 days each. Budesonide (200 microg b.i.d) was administered via a Nebuchamber or fluticasone (125 microg b.i.d) via a Babyhaler. Aerosol was trapped in filters, positioned between the spacer and face mask. Cooperation was scored on diary cards. Electrostatic charge (ESC) of the spacers was measured. Evaluations of the administration technique were made from video recordings. Median (range) dose delivery of the filters expressed as per cent (%) of nominal dose, was 34% (3-59), 23% (1-49), and 41% (12-55) for the Nebuchamber, nonDC-Babyhaler, and DC-Babyhaler respectively. Considerable dose variability was found, median (range) within-subject dose variability, expressed as coefficient of variation, for the Nebuchamber (49% (15-249)) was significantly higher when compared with both nonDC- (36% (12-325)) and DC-Babyhalers (27% (10-122)), for which dose variabilities were similar. Detergent coating was effective to reduce electrostatic charge, and to increase dose delivery, but had no effect on dose variability. Bad cooperation was an important cause for high dose variability for all spacers (r=0.5-0.6, p<0.02). Many mistakes were made during the administration procedure.