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Aims: Knowledge about adverse drug events caused by drug-drug interactions (DDI-ADEs) is limited. We aimed to provide detailed insights about DDI-ADEs related to three frequent, high-risk potential DDIs (pDDIs) in the critical care setting: pDDIs with international normalized ratio increase (INR + ) potential, pDDIs with acute kidney injury (AKI) potential, and pDDIs with QTc prolongation potential., Methods: We extracted routinely collected retrospective data from electronic health records of intensive care units (ICUs) patients (≥18 years), admitted to ten hospitals in the Netherlands between January 2010 and September 2019. We used computerized triggers (e-triggers) to preselect patients with potential DDI-ADEs. Between September 2020 and October 2021, clinical experts conducted a retrospective manual patient chart review on a subset of preselected patients, and assessed causality, severity, preventability, and contribution to ICU length of stay of DDI-ADEs using internationally prevailing standards., Results: In total 85 422 patients with ≥1 pDDI were included. Of these patients, 32 820 (38.4%) have been exposed to one of the three pDDIs. In the exposed group, 1141 (3.5%) patients were preselected using e-triggers. Of 237 patients (21%) assessed, 155 (65.4%) experienced an actual DDI-ADE; 52.9% had severity level of serious or higher, 75.5% were preventable, and 19.3% contributed to a longer ICU length of stay. The positive predictive value was the highest for DDI-INR + e-trigger (0.76), followed by DDI-AKI e-trigger (0.57)., Conclusion: The highly preventable nature and severity of DDI-ADEs, calls for action to optimize ICU patient safety. Use of e-triggers proved to be a promising preselection strategy., (© 2023 The Authors. British Journal of Clinical Pharmacology published by John Wiley & Sons Ltd on behalf of British Pharmacological Society.)

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.

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., (Copyright © 2019 Elsevier Ltd. All rights reserved.)

Background: A necrotizing soft-tissue infection (NSTI) is a rare but severe infection with a high mortality rate of 12%-20%. Diagnosing is challenging and often delayed. Treatment consists of surgical debridement of all necrotic tissue and administration of antibiotics. Despite adequate treatment, survivors are often left with extensive wounds, resulting in mutilating scars and functional deficits. Both the disease and the subsequent scars can negatively influence the health-related quality of life (HRQoL). The present study was performed to contribute to the knowledge about HRQoL in patients after NSTI., Methods: We retrospectively identified patients treated for NSTI in a tertiary center in the Netherlands. Patient and treatment characteristics were collected and patients were asked to fill in a Short Form 36 questionnaire., Results: Forty-six patients with a diagnosis of NSTI were identified. Twenty-eight (61%) were male and mean age was 57 y. Thirty-nine patients (80%) survived. Thirty-one (84%) of the survivors returned the questionnaire after a median follow-up of 4.1 y (interquartile range [IQR], 2.4-5.9 y). Statistically significantly decreased scores when compared to the Dutch reference values were observed for the Short Form 36 domains, physical functioning, role-physical functioning, general health, and the combined Physical Component Score. No differences were observed for the other five domains or for the Mental Component Score., Conclusions: This study confirms that NSTI negatively affects HRQoL as reported by the patient, especially on the physical domains. To learn more about HRQoL in patients after NSTI, studies in larger groups with a more disease-specific questionnaire should be performed., Level of Evidence: Level 3, prognostic and epidemiological., (Copyright © 2019 Elsevier Inc. All rights reserved.)

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.

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.

Epidermal inclusion cysts are common epithelial cysts of the skin. The latter classically originate from progressive cystic ectasia of the infundibular portion of hair follicle. Therefore, these cysts are usually found in hairy regions and rarely in glabrous skin such as the palms and soles. The etiology of glabrous epidermal inclusion cysts appear to be different from that of those located in hairy regions. It has been suggested that implantation of epithelial cells into subcutaneous tissue, such as during trauma, is most likely the pathophysiologic basis. Epidermal inclusion cysts on the palms and soles are often misdiagnosed, leading to improper treatment. Therefore, we report a rare case of an epidermal inclusion cyst of the heel after minimally invasive surgery of a displaced intra-articular calcaneal fracture., (Copyright © 2018 The American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

The published online version contain mistake in the author list for the name of the author "J. Carel Goslings" was incorrectly presented in the HTML version.

Purpose: Infectious complications following lower extremity fracture surgery are a major concern and account for a substantial socio-economic burden to society. The aim of this pilot study was to investigate the feasibility of a new portable single-use negative pressure wound therapy device in patients undergoing major foot ankle surgery., Methods: Patients undergoing major foot ankle fracture surgery at a single level 1 trauma centre were eligible for this prospective case series. Patient characteristics were collected, as were fracture and surgical characteristics. Primary outcome was surgical site infection within 30 days as classified by the criteria from the Centers for Disease Control and Prevention. Patients in the prospective cohort were case-matched with a historical cohort from the same institution., Results: Sixty patients were included. In seven patients, the NPWT failed and treatment was ceased. Mean age was 44 years and 85% was ASA 1; 43% of the patients were actively smoking. Indications for surgery were midfoot, calcaneal, talar, and ankle fractures. In 53 patients, four (7.5%) surgical site infections occurred, two superficial (3.3%) and two (3.3%) deep infections. For 47 patients, a match was available. The incidence of surgical site infection did not statistically significantly differ between the prospective cohort and retrospective matched cohort (4.3 versus 14.9%, p = 0.29, respectively). This was also the case when looking at superficial and deep surgical site infections separately (0 versus 8.5%, p = 0.08, and 4.3 versus 6.4%, respectively)., Conclusion: We have observed surgical site infections in 7.5% of the patients with the use of prophylactic negative pressure wound therapy. The incidence of surgical site infections was not statistically significantly lower compared to a matched historical cohort.

Background: 18 F-fluorodeoxyglucose ( 18 F-FDG) positron emission tomography (PET)/computed tomography (CT) has proven to have a high diagnostic accuracy for the detection of bone infections. In patients with delayed union it may be clinically important to differentiate between aseptic and septic delayed union. The aim of this study was to evaluate the efficacy and to assess the optimal diagnostic accuracy of FDG-PET/CT in differentiating between aseptic and septic delayed union in the lower extremity., Methods: This is a retrospective study of consecutive patients who underwent FDG-PET/CT scanning for suspicion of septic delayed union of the lower extremity. Diagnosis of aseptic delayed union or septic delayed union was made based on surgical deep cultures following PET/CT scanning and information on clinical follow-up. FDG-uptake values were measured at the fractured site by use of the maximum standardized uptake value (SUV max ). Sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were calculated at various SUV max cut-off points., Results: A total of 30 patients were included; 13 patients with aseptic delayed unions and 17 patients with septic delayed unions. Mean SUV max in aseptic delayed union patients was 3.23 (SD ± 1.21). Mean SUV max in septic delayed union patients was 4.77 (SD ± 1.87). A cut-off SUV max set at 4.0 showed sensitivity, specificity and diagnostic accuracy of FDG-PET/CT were 65, 77 and 70% to differentiate between aseptic and septic delayed union, respectively., Conclusion: Using a semi-quantitative measure (SUV max ) for interpretation of FDG-PET/CT imaging seems to be a promising tool for the discrimination between aseptic and septic delayed union.

Calcaneal fractures are notoriously difficult to treat and wound complications occur often. However, owing to the rare nature of these fractures, clinical trials on this subject are lacking. Thus, biomechanical studies form a viable source of information on this subject. With our systematic review of biomechanical studies, we aimed to provide an overview of all the techniques available and guide clinicians in their choice of method of fracture fixation. A literature search was conducted using 3 online databases to find biomechanical studies investigating methods of fixation for calcaneal fractures. A total of 14 studies investigating 237 specimens were identified. Large diversity was found in the tested fixation methods and in the test setups used. None of the studies found a significant difference in favor of any of the fixation methods. All tested methods provided a biomechanically stable fixation. All the investigated methods of fixation for calcaneal fractures seem to be biomechanically sufficient. No clear benefit was found for locking plates in the fixation of calcaneal fractures; however, a subtle mechanical superiority might exist compared with nonlocking plates in the case of fractures in osteoporotic bone. Several of the techniques tested would be suitable for a minimal invasive approach. These should be investigated further in clinical trials., (Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Background: Calcaneal fractures are uncommon and have a substantial impact on hindfoot function and quality of life. Several surgical treatment options are available; both in surgical approach and type of operation. The aim of this study was to compare functional outcome and quality of life following ORIF and primary arthrodesis. Furthermore, predictors of worse functional outcome were explored., Methods: A retrospective cross-sectional cohort study was performed in patients with surgical fixation of a calcaneal fracture with a minimum follow-up of 18 months. Patients received ORIF through the 1) Extended Lateral Approach (ELA), 2) Sinus Tarsi Approach (STA) or 3) primary arthrodesis via STA. Participants were presented a questionnaire containing demographics, the AOFAS hindfoot scale, Foot Function Index, SF-36, EQ-5D and patient satisfaction., Results: In total 95 patients participated in this study. The three groups were comparable regarding patient characteristics. A median score of 74.5 points on the AOFAS hindfoot scale and 11.9 on the FFI was found for the entire group. There were no statistically significant differences between patients with ORIF of primary arthrodesis. Patients scored a median of 49.0 on the Physical Component Scale of the SF-36 and 55.4 on the Mental Component Scale. On the EQ-5D patients scored a median of 0.8 points. Again no statistically significant differences were observed between the three subgroups. Socio-economic status was the only statistically significant predictor of worse functional outcome (β: 4.06, 95% CI: 0.50-7.62) after multivariable analysis., Interpretation: Good midterm outcomes following in terms of functional outcome and in quality of life are observed. We observed no statistical significant difference in functional outcome between patients with ORIF and patients with primary arthrodesis. The only predictor of worse functional outcome is a lower socio-economic status., (Copyright © 2017 Elsevier Ltd. All rights reserved.)

The current reference standard for unstable ankle fractures is open reduction and internal fixation using a plate and lag screws. This approach requires extensive dissection and wound complications are not uncommon. The use of intramedullary screw fixation might overcome these issues. The aim of our study was to provide an overview of the published data regarding intramedullary screw fixation of fibula fractures combined with a small consecutive case series. We performed a search of published studies to identify the studies in which fibula fractures were treated with percutaneous intramedullary screw fixation. Additionally, all consecutive patients treated for an unstable ankle fracture in a level 1 trauma center using an intramedullary screw were retrospectively included. The literature search identified 6 studies with a total of 180 patients. Wound infection was seen in 1 patient (0.6%), anatomic reduction was achieved in 168 patients (93.3%), and a loss of reduction was seen in 2 patients (1.1%). Implant removal was deemed necessary in 3 patients (1.7%) and nonunion was seen is 2 patients (1.1%). A total of 11 patients, in whom no wound complications occurred, were included in our study. The follow-up duration was a minimum of 12 months. A secondary dislocation was seen in 1 patient, and delayed union was observed after 7.5 months in 1 other patient. In conclusion, intramedullary screw fixation is a safe and adequate method to use for fibula fractures, with a low risk of wound complications. Additional research regarding functional outcome is warranted., (Copyright © 2017 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

Objectives: To investigate whether the sinus tarsi approach (STA) allows for a similar anatomical reduction of the posterior talocalcaneal facet as the extended lateral approach (ELA) and compare the rate of postoperative wound complications., Design: Retrospective., Setting: Level 1 trauma center., Patients: All consecutive patients from 2012 to 2015 with a closed displaced intra-articular calcaneal fracture Sanders type II and III surgically treated with the ELA (N = 60) and the STA (N = 65)., Main Outcome Measurements: Wound complications, timing of surgery, operative time, length of postoperative hospitalization, and reduction of the posterior facet and calcaneal body., Results: Incidence of wound complications, time to surgery, postoperative duration of hospital admission, and number of hospital admissions because of wound complications were significantly different between the ELA group and STA group. There was no significant difference in restoration of calcaneal anatomy with either approach. Importantly, the STA was performed in a median duration of 105 minutes and the ELA in a median of 134 minutes, accounting for nearly half an hour difference in operating time (P < 0.001)., Conclusions: The largest benefit of the STA was found in the significant reduction in wound complications and operative time, where time to closure may have accounted for the latter difference. This difference was without a compromise in reduction. Additional studies comparing functional outcome, especially rates of subtalar arthrosis, will be needed to determine the long-term benefits of STA., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence.

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.

Objective: The objective of the present study was (1) to identify predictors of both nonunion and postoperative wound infections (POWI) and (2) to assess the union and complication rate following posttraumatic subtalar arthrodesis (STA)., Design: Retrospective comparative cohort study., Setting: Level 1 trauma center., Patients: All consecutive adult patients with STA following traumatic injuries between 2000 and May 2015., Intervention: STA for posttraumatic deformities., Main Outcome Measurements: Union (described as a combination of radiographic signs of osseous bridging and a clinically fused joint) and POWI as classified by the Centers for Disease and Control., Results: A total number of 93 (96 feet) patients met the inclusion criteria. Union was achieved in 89% of patients. For primary, secondary in situ, and secondary correction arthrodesis, these percentages were 94%, 84,% and 90%, respectively (NS). The union rate significantly increased over time (P = 0.02). In 17 patients (18%), a POWI occurred, of which 2 were classified as superficial and 15 as deep POWIs. The POWI rate did not differ between the groups. Alcohol, nicotine, and drug abuse were not significantly associated with the occurrence of POWIs. Patients with an open fracture or an infection following open reduction internal fixation had a greater risk of a POWI following STA (P = 0.03 and P = 0.04, respectively)., Conclusions: We could not identify predictors for nonunion. In 18% of the patients, an infectious complication following surgery occurred. Patients with an open fracture or an infection after primary surgical treatment (ie, open reduction internal fixation) have a higher chance of POWIs following STA. The union rate following posttraumatic STA is 89%., Level of Evidence: Therapeutic Level IV. See Instructions for Authors for a complete description of levels of evidence.

The standard operative treatment of Lisfranc fracture dislocations currently consists of open reduction and transarticular fixation. Recently, bridge plating has been used more often. Using joint spanning, the reduced fracture dislocation is temporary stabilized to minimize articular damage. The present study describes the outcomes of patients treated with bridge plating after tarsometatarsal fracture dislocations compared with transarticular screw fixation. A retrospective cohort study was performed. Patients with an isolated tarsometatarsal injury who had been treated operatively from June 2000 to October 2013 were included. The primary functional outcome was measured using the American Orthopaedic Foot and Ankle Society midfoot score and the Foot Function Index. The secondary outcome was patient satisfaction, which was measured using the EuroQol 5 dimensions questionnaire and a visual analog scale. A total of 34 patients were included. Bridge plating was used in 21 patients. In 13 patients, Kirschner wires or transarticular screws or a combination were used. The median follow-up period was 49 (interquartile range 18 to 89) months. The implants were removed in 10 of 13 patients in the transarticular group and 17 of 21 patients in the bridge plating group. The incidence of wound complications was comparable in both groups. The median American Orthopaedic Foot and Ankle Society score was lower in the transarticular group (77 versus 66). The Foot Function Index score was 18 in both groups. Patient satisfaction was 90% in the bridge plating group and 80% in the transarticular group. Bridge plating for Lisfranc injuries led to at least similar results compared with transarticular fixation in terms of functional outcomes and patient satisfaction. Longer follow-up is necessary to determine whether the prevention of secondary damage to the articular surface leads to less post-traumatic arthritis and better functional outcomes., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

The most important goal of surgical management of displaced intra-articular calcaneal fractures is anatomic correction. This reduction is usually stabilized using plate and screw osteosynthesis. In addition, Kirschner wires (K-wires) can be used to maintain the surgical reduction or stability of the construct. In the present study, we evaluated the frequency and type of use of additional K-wires and subsequent migration in the surgical management of displaced intra-articular calcaneal fractures. The data from 279 patients treated surgically from January 1, 2000 to December 31, 2014 in a level 1 trauma center using an extended lateral approach were analyzed after 1 year of follow-up. All postoperative radiographic images were reviewed to identify the cases in which K-wires were used. Data on the number and type of K-wires used, K-wire location, and K-wire migration found on follow-up imaging studies were collected. Of the 279 patients, 69 K-wires had been used in 49 (18%) patients. A total of 25 (36%) lost (buried), 38 (55%) bent, and 6 (9%) unmodified straight K-wires had been placed. Overall, in 4 (5.8%) of 69 K-wires, secondary dislocation was seen. One (4%) of the lost, 3 (50%) of the unmodified, and none of the bent K-wires showed secondary dislocation. K-wire migration was seen in 5.8% of the cases. None of the bent K-wires and only 1 of the lost K-wires had migrated in the present study. These 2 techniques are preferred when using K-wire fixation in the treatment of displaced intra-articular calcaneal fractures. The use of unmodified straight K-wires should be discouraged., (Copyright © 2016 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Introduction: Fluorine-18 fluorodeoxyglucose (F-FDG) PET/computed tomography (CT) has proven to be a valuable imaging modality with high diagnostic accuracy for the detection of bone infections. However, the physiological uptake values for F-FDG in the long bones of the lower extremity have not been established yet. This hampers correct interpretation of a F-FDG-PET/CT scan., Purpose: The purpose of this study was to determine the physiological uptake values of F-FDG in the long bones of the lower extremities, including the femur and the tibia., Patients and Methods: We retrospectively analyzed the F-FDG-PET/CT scan of 84 consecutive patients from our database. F-FDG uptake parameters included mean standardized uptake value (SUVmean) and maximum standardized uptake value (SUVmax). Both SUVs were determined in the diaphyseal region of the femur and the tibia., Results: SUVmean for the femoral diaphysis was 0.46 [95% confidence interval (CI) 0.42-0.49] and SUVmax was 0.81 (95% CI 0.74-0.88). For the tibial diaphysis, SUVmean was 0.34 (95% CI 0.32-0.37) and SUVmax was 0.61 (95% CI 0.56-0.65). SUVmean and SUVmax of the femur were significantly higher than that of the tibia (both P<0.01). SUVs for men were not significantly different from that for women and did not discriminate between age classes., Conclusion: For a correct interpretation of the F-FDG-PET/CT scan, we have determined the F-FDG uptake values in the long bones of the femur and the tibia. A SUVmean less than 0.5 and a SUVmax less than 0.8 can be considered as normal bone, irrespective of sex or age.

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.

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.

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., (Copyright © 2014 Elsevier Ltd. All rights reserved.)

Background: Frostbite is an uncommon event that can occur from exposure to temperatures below -4 degrees C and can lead to potential serious tissue damage and necrosis. This in turn can result in debilitating amputations in otherwise healthy people. The pathophysiological mechanisms of frostbite have marked similarities to those seen in thermal burns, ischemia/reperfusion injuries and crush injuries--i.e., non-healing wounds and inflammatory processes. These injuries are commonly treated with hyperbaric oxygen therapy., Objectives: Evidence for treating frostbite with hyperbaric oxygen (HBO2) is scarce, and to date HBO2 is not a standard addition in the multidisciplinary care of freezing injuries. We aim to contribute to the available evidence with a case report and review the literature to reassess the multidisciplinary treatment of frostbite injuries., Case Report and Review of Literature: We present a case report of a woman with deep frostbite of the toes treated with hyperbaric oxygen therapy, after a delay of 21 days, with good results. No surgical intervention was needed. A literature search revealed 17 human case reports on frostbite and four animal studies in which hyperbaric oxygen was applied. All case reports showed positive effects, and in none of the cases was amputation necessary. In the animal studies, two showed significant positive results regarding tissue loss and reduction of inflammatory markers, whereas two did not., Conclusions: Based on our case report as well as the literature and the mechanisms of hyperbaric oxygen, we make the recommendation that this therapy be considered as an addition to the multidisciplinary treatment of frostbite, even after significant delay of treatment.

Aims/hypothesis: Thymic expression of self-antigens during T-lymphocyte development is believed to be crucial for preventing autoimmunity. It has been suggested that G6PC2, the gene encoding islet-specific glucose-6-phosphatase catalytic subunit-related protein (IGRP), is differentially spliced between pancreatic beta cells and the thymus. This may contribute to incomplete elimination of IGRP-specific T lymphocytes in the thymus, predisposing individuals to type 1 diabetes. We tested whether specific splice variation in islets vs thymus correlates with loss of tolerance to IGRP in type 1 diabetes., Methods: Expression of G6PC2 splice variants was compared among thymus, purified medullary thymic epithelial cells and pancreatic islets by RT-PCR. Differential immunogenicity of IGRP splice variants was tested in patients and healthy individuals for autoantibodies and specific cytotoxic T lymphocytes using radiobinding assays and HLA class I multimers, respectively., Results: Previously reported G6PC2 splice variants, including full-length G6PC2, were confirmed, albeit that they occurred in both pancreas and thymus, rather than islets alone. Yet, their expression levels were profoundly greater in islets than in thymus. Moreover, three novel G6PC2 variants were discovered that occur in islets only, leading to protein truncations, frame shifts and neo-sequences prone to immunogenicity. However, autoantibodies to novel or known IGRP splice variants did not differ between patients and healthy individuals, and similar frequencies of IGRP-specific cytotoxic T lymphocytes could be detected in both patients with type 1 diabetes and healthy individuals., Conclusions/interpretation: We propose that post-transcriptional variation of tissue-specific self-proteins may affect negative thymic selection, although this need not necessarily lead to disease.

For ankle fractures, in general, several studies have been published on immobilization (e.g., cast or boot) versus early motion after surgical treatment. However, no studies have been performed to determine the best aftercare strategy for surgically treated patients with ankle fractures with concomitant acute distal tibiofibular syndesmotic injuries. The aim of the present review was to compare the functional outcomes of ankle fractures with syndesmotic injury treated with a cast or boot versus early motion. We performed a systematic review using the electronic databases from January 1, 2000 to September 1, 2012 of the Cochrane Library, PubMed MEDLINE(®), EMbase, and Google Scholar. The included studies were those in which ankle fractures with acute distal tibiofibular syndesmotic injuries had been treated with 1 or more syndesmotic screws, with a mean follow-up period of at least 12 months and at least 25 patients included. The functional outcomes, measured using the American Orthopaedic Foot Ankle Society Hindfoot scale, Olerud-Molander Ankle Scale, and Short Musculoskeletal Function Assessment, were compared. A total of 9 studies were identified with a total of 531 patients. The number of included patients ranged from 28 to 93. The mean follow-up period was 12 to 101 months. Of the 9 studies, 3 used an early motion protocol (195 patients) and 6 (336 patients) a protocol of immobilization for at least 6 weeks. For the American Orthopaedic Foot Ankle Society Hindfoot scale, the mean scores for immobilization were 86 to 91 points and for early motion, 84 to 89. For the Olerud-Molander Ankle Scale, the scores for immobilization were 47 to 90 and for early motion, 46 to 82 points. The Short Musculoskeletal Function Assessment score for immobilization was 11 and for early motion ranged from 12 to 27 points. No apparent differences could be detected in the published data considering the functional outcomes between immobilization versus an early motion protocol in ankle fractures with acute distal tibiofibular syndesmotic injuries treated with a syndesmotic screw. However, level 1 and 2 studies on this subject are lacking., (Copyright © 2013 American College of Foot and Ankle Surgeons. Published by Elsevier Inc. All rights reserved.)

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.

Necrotising soft-tissue infections occur in the soft tissue compartment consisting of the dermis, subcutaneous tissue, superficial fascia (fascia of Scarpa), deep fascia and muscle. Although this severe and acutely life-threatening infection has a low incidence, both GPs and specialists will see a necrotizing soft-tissue infection more than once during their career. The mortality related to necrotising soft-tissue infections has been halved during the past 15 years from nearly 40 to 20% due to adequate treatment. Laboratory examination and X-ray findings could be of added value, but the gold standard remains biopsy of the fascia and Gram staining. Treatment consists of prompt volume resuscitation in case of sepsis, administration of broad spectrum antibiotics and surgical debridement; this debridement should be as skin-sparing as possible. The use of hyperbaric oxygen therapy has remained a controversial issue, unless a patient has gas gangrene, caused by Clostridium species. A multidisciplinary treatment and admission to a tertiary intensive care unit are indispensable for the treatment of a septic patient with necrotizing soft-tissue infection.

Frostbite injuries rarely occur in healthy Dutch persons. However, as the number of people engaging in winter and outdoor activities and travelling to high altitudes increases, the risk of frostbite also increases. Frostbite is a cold-induced injury which results from two processes: freezing and microvascular occlusion. Adequate first aid, which focuses on the prevention of refreezing and mechanical injury, and rapid rewarming together with the administration of ibuprofen, are of the greatest importance for limiting eventual tissue damage. Iloprost infusion and possibly (r)tPA are indicated if a patient presents within 24 hours after the tissue has thawed and the injury is such that severe morbidity can be expected. If the patient presents after this time period, hyperbaric oxygen therapy may be considered; however, the evidence available on this type of treatment is limited.

We present three patients, a 55-year-old man, a 69-year-old woman and a 25-year-old man, with a seatbelt sign following a car accident. All 3 patients exhibited various injuries that may occur in the case of a blunt trauma, for example rib fractures. In one patient, however, symptoms of internal abdominal injury occurred several days after the accident. The presence of a seatbelt sign is associated with an increased risk of internal abdominal injury. We therefore advise a CT scan of the abdomen in patients who present with a seatbelt sign, even if abdominal ultrasound does not reveal signs of injury.

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.

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

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.

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.

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.

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.