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Objectives: There is debate about when to start exercises in the nonoperative treatment of a proximal humerus fracture. This randomized trial compared immediate and one-month delayed shoulder exercises in the nonoperative treatment of fractures of the proximal humerus., Methods: Twenty-six patients with a fracture of the proximal humerus who chose nonoperative treatment were randomized to start pendulum exercises within a few days and 24 were randomized to delayed exercises and started with active self-assisted stretching 1 month after fracture. Three and six months after the injury, patients completed the Disabilities of the Arm Shoulder and Hand questionnaire to measure capability, a measure of pain intensity, and had motion measurements., Results: There was no significant difference in forward flexion (primary outcome) six months after injury between patients that started motion exercises immediately compared to 1 month after injury (p = 0.85). There was no difference in any motion measurement, pain intensity, upper extremity specific disability (DASH score) three or six months after injury., Conclusion: Delaying exercises for a month does not affect recovery from nonoperative treatment of a fracture of the proximal humerus. People can choose whether to start exercises immediately or wait until they feel comfortable., Competing Interests: None

Purpose: The healthcare sector is responsible for 6-7% of CO 2 emissions. The intensive care unit (ICU) contributes to these CO 2 emissions and a shift from a linear system to a circular system is needed. The aim of our research was to perform a material flow analysis (MFA) in an academic ICU. Secondary aims were to obtain information and numbers on mass, carbon footprint, agricultural land occupation and water usage and to determine so-called "environmental hotspots" in the ICU., Methods: A material flow analysis was performed over the year 2019, followed by an environmental footprint analysis of materials and environmental hotspot identification., Results: 2839 patients were admitted to our ICU in 2019. The average length of stay was 4.6 days. Our MFA showed a material mass inflow of 247,000 kg in 2019 for intensive care, of which 50,000 kg is incinerated as (hazardous) hospital waste. The environmental impact per patient resulted in 17 kg of mass, 12 kg CO 2 eq, 300 L of water usage and 4 m 2 of agricultural land occupation per day. Five hotspots were identified: non-sterile gloves, isolation gowns, bed liners, surgical masks and syringes (including packaging)., Conclusion: This is the first material flow analysis that identified environmental risks and its magnitude in the intensive care unit., (© 2022. The Author(s).)

Objectives: Glucocorticoid-induced adrenal insufficiency (GI-AI) is a common side effect of glucocorticoid therapy. However, its diagnosis currently relies on the realization of a Low Dose Short Synacthen Test (LD-SST) that requires an outpatient hospital and several blood samples. Our goal was to evaluate whether morning cortisol values could predict the response to LD-SST, in children, to avoid useless dynamic tests and facilitate diagnosis of glucocorticoid induced adrenal insufficiency., Study Design: We recorded data of 91 pediatric patients who underwent a LD-SST in our center between 2016 and 2020 in a retrospective observational study. We selected LD-SST realized following administration of supra-physiologic doses of glucocorticoids during more than 3 weeks and performed at least four weeks after treatment was stopped. Adrenal deficiency was defined as a plasma cortisol concentration inferior to 500 nmol/l at LD-SST., Results: Glucocorticoid-induced adrenal insufficiency was diagnosed in 60% of our cohort. Morning cortisol values were predictive of the response to the LD-SST (AUC ROC 0.78). A plasma cortisol concentration of less than 144 nmol/l predicted glucocorticoid induced adrenal insufficiency with a specificity of 94% and a value over 317 nmol/l predicted recovery of the HPA axis with a sensitivity of 95%. We did not find any other predictive factor for glucocorticoid-induced adrenal insufficiency., Conclusions: Morning cortisol values can safely assess recovery of the HPA axis in children treated chronically with glucocorticoids. Using these thresholds, more than 50% of LD-SST could be avoided in children., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (© 2022 Laulhé, Dumaine, Chevenne, Leye, Faye, Dozières, Strullu, Viala, Hogan, Houdouin, Léger, Simon, Carel, Storey, Guilmin-Crépon and Martinerie.)

Conventional microscopy is the standard procedure for the diagnosis of schistosomiasis, despite its limited sensitivity, reliance on skilled personnel, and the fact that it is error prone. Here, we report the performance of the innovative (semi-)automated Schistoscope 5.0 for optical digital detection and quantification of Schistosoma haematobium eggs in urine, using conventional microscopy as the reference standard. At baseline, 487 participants in a rural setting in Nigeria were assessed, of which 166 (34.1%) tested S. haematobium positive by conventional microscopy. Captured images from the Schistoscope 5.0 were analyzed manually (semiautomation) and by an artificial intelligence (AI) algorithm (full automation). Semi- and fully automated digital microscopy showed comparable sensitivities of 80.1% (95% confidence interval [CI]: 73.2-86.0) and 87.3% (95% CI: 81.3-92.0), but a significant difference in specificity of 95.3% (95% CI: 92.4-97.4) and 48.9% (95% CI: 43.3-55.0), respectively. Overall, estimated egg counts of semi- and fully automated digital microscopy correlated significantly with the egg counts of conventional microscopy (r = 0.90 and r = 0.80, respectively, P < 0.001), although the fully automated procedure generally underestimated the higher egg counts. In 38 egg positive cases, an additional urine sample was examined 10 days after praziquantel treatment, showing a similar cure rate and egg reduction rate when comparing conventional microscopy with semiautomated digital microscopy. In this first extensive field evaluation, we found the semiautomated Schistoscope 5.0 to be a promising tool for the detection and monitoring of S. haematobium infection, although further improvement of the AI algorithm for full automation is required.

Urinary schistosomiasis is a waterborne parasitic infection caused by Schistosoma haematobium that affects approximately 30 million people annually in Nigeria. Treatment and eradication of this infection require effective diagnostics. However, current diagnostic tests have critical shortcomings and consequently are of limited value to stakeholders throughout the health care system who are involved in targeting the diagnosis and subsequent control of schistosomiasis. New diagnostic devices that fit the local health care infrastructure and support the different stakeholder diagnostic strategies remain a critical need. This study focuses on understanding, by means of Q-methodology, the context of use and application of a new diagnostic device that is needed to effectively diagnose urinary schistosomiasis in Oyo State, Nigeria. Q-methodology is a technique that investigates subjectivity by exploring how stakeholders rank-order opinion statements about a phenomenon. In this study, 40 statements were administered to evaluate stakeholder perspectives on the context of use and application of potential new diagnostic devices and how these perspectives or viewpoints are shared with other stakeholders. Potential new diagnostic devices will need to be deployable to remote or distant communities, be affordable, identify and confirm infection status before treatment in patients whose diagnosis of urinary schistosomiasis is based on self-reporting, and equip health care facilities with diagnostic devices optimized for the local setting while requiring local minimal infrastructural settings. Similarly, the context of use and application of a potential new diagnostic device for urinary schistosomiasis is primarily associated with the tasks stakeholders throughout the health care system perform or procedures employed. These findings will guide the development of new diagnostic devices for schistosomiasis that match the contextual landscape and diagnostic strategies in Oyo., (© Samenjo et al.)

Introduction: Traumatic injuries of the shoulder or chest wall are commonly treated in the Emergency Department (ED). A complementary treatment is kinesiotaping, an elastic tape often used to treat musculoskeletal dysfunction and pain. However, the added pain-reducing effect of kinesiotape in comparison to standard conservative treatment is unknown. The aim of this study was to determine the effect of kinesiotaping on pain relief compared to standard treatment with pain medication and immobilization in patients with uncomplicated traumatic injury of the shoulder or chest wall in the ED., Method: A pilot randomized controlled trial (RCT) was conducted in the ED of a teaching hospital in the Netherlands from January 2021 until the end of March 2021. Patients diagnosed with uncomplicated isolated rib fractures, rib contusions, clavicle fracture, disruption of the AC joint and fracture of the proximal humerus were assigned to two treatment groups. The control group received the standard treatment with oral analgesics (acetaminophen q6h 1000 mg and NSAID (according to prescription) and if shoulder injury also a sling. The intervention group received kinesiotaping in addition to the same standard treatment. Pain intensity was measured with 0-10 Numeric Rating Scale (NRS) just before treatment (T1) and after 15 min (T2). On day 4 both groups were assessed with NRS in a follow up phone call (T3)., Results: A total of 251 patients presented with traumatic injury of the shoulder or chest wall in the study period, 85 patients were approached to participate and 2 of them were excluded. The remaining 83 were randomly allocated to kinesiotaping (n = 40) or control group (n = 43), 57 of them completed the study and had sufficient data for complete analysis In both groups, pain intensity after 15 min and 4 days significantly reduced compared with baseline. Regarding the reduction of pain intensity on day 4, kinesiotaping was significantly superior compared to the control group with a difference in pain reduction of 2.45 compared with 0.88 in control group (p = 0.018)., Conclusion: Compared to standard treatment alone, kinesiotaping combined with standard care appears to be more effective in terms of acute pain reduction in patients with uncomplicated traumatic injury of the shoulder or chest wall. Further research is recommended., Competing Interests: Declaration of Competing Interest Authors declare that they have no conflict of interest. This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors., (Copyright © 2022 The Authors. Published by Elsevier Inc. All rights reserved.)

Turner syndrome (TS; ORPHA 881) is a rare condition in which all or part of one X chromosome is absent from some or all cells. It affects approximately one in every 1/2500 liveborn girls. The most frequently observed karyotypes are 45,X (40-50%) and the 45,X/46,XX mosaic karyotype (15-25%). Karyotypes with an X isochromosome (45,X/46,isoXq or 45,X/46,isoXp), a Y chromosome, X ring chromosome or deletions of the X chromosome are less frequent. The objective of the French National Diagnosis and Care Protocol (PNDS; Protocole National de Diagnostic et de Soins) is to provide health professionals with information about the optimal management and care for patients, based on a critical literature review and multidisciplinary expert consensus. The PNDS, written by members of the French National Reference Center for Rare Growth and Developmental Endocrine disorders, is available from the French Health Authority website. Turner Syndrome is associated with several phenotypic conditions and a higher risk of comorbidity. The most frequently reported features are growth retardation with short adult stature and gonadal dysgenesis. TS may be associated with various congenital (heart and kidney) or acquired diseases (autoimmune thyroid disease, celiac disease, hearing loss, overweight/obesity, glucose intolerance/type 2 diabetes, dyslipidemia, cardiovascular complications and liver dysfunction). Most of the clinical traits of TS are due to the haploinsufficiency of various genes on the X chromosome, particularly those in the pseudoautosomal regions (PAR 1 and PAR 2), which normally escape the physiological process of X inactivation, although other regions may also be implicated. The management of patients with TS requires collaboration between several healthcare providers. The attending physician, in collaboration with the national care network, will ensure that the patient receives optimal care through regular follow-up and screening. The various elements of this PNDS are designed to provide such support., (© 2022. The Author(s).)

Objective: To look at the association of socioeconomic status (SES) with the suitability of the maternity where children are born and its association with mortality., Design: Retrospective analysis of a prospective cohort constituted using hospital discharge databases., Setting: France POPULATION: Live births in 2012-2014 in maternity hospitals in mainland France followed until discharge from the hospital., Main Outcome Measure: Unsuitability of the maternity to newborns' needs based on birth weight and gestational age, early transfers (within 24 hours of birth) and in-hospital mortality., Results: 2 149 454 births were included, among which 155 646 (7.2%) were preterm. Preterm newborns with low SES were less frequently born in level III maternities than those with high SES. They had higher odds of being born in an unsuitable maternity (OR=1.174, 95% CI 1.114 to 1.238 in the lowest SES quintile compared with the highest), and no increase in the odds of an early transfer (OR=0.966, 95% CI 0.849 to 1.099 in the lowest SES quintile compared with the highest). Overall, newborns from the lowest SES quintile had a 40% increase in their odds of dying compared with the highest (OR=1.399, 95% CI 1.235 to 1.584)., Conclusions: Newborns with the lowest SES were less likely to be born in level III maternity hospitals compared with those with the highest SES, despite having higher prematurity rates. This was associated with a significantly higher mortality in newborns with the lowest SES. Strategies must be developed to increase health equity among mothers and newborns., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. No commercial re-use. See rights and permissions. Published by BMJ.)

Aims/hypothesis: Caused by biallelic mutations of the gene encoding the transcription factor RFX6 , the rare Mitchell-Riley syndrome (MRS) comprises neonatal diabetes, pancreatic hypoplasia, gallbladder agenesis or hypoplasia, duodenal atresia, and severe chronic diarrhea. So far, sixteen cases have been reported, all with a poor prognosis. This study discusses the multidisciplinary intensive clinical management of 4 new cases of MRS that survived over the first 2 years of life. Moreover, it demonstrates how the mutations impair the RFX6 function., Methods: Clinical records were analyzed and described in detail. The functional impact of two RFX6 R181W and RFX6 V506G variants was assessed by measuring their ability to transactivate insulin transcription and genes that encode the L-type calcium channels required for normal pancreatic beta-cell function., Results: All four patients were small for gestational age (SGA) and prenatally diagnosed with duodenal atresia. They presented with neonatal diabetes early in life and were treated with intravenous insulin therapy before switching to subcutaneous insulin pump therapy. All patients faced recurrent hypoglycemic episodes, exacerbated when parenteral nutrition (PN) was disconnected. A sensor-augmented insulin pump therapy with a predictive low-glucose suspension system was installed with good results. One patient had a homozygous c.1517T>G (p.Val506Gly) mutation, two patients had a homozygous p.Arg181Trp mutation, and one patient presented with new compound heterozygosity. The RFX6 V506G and RFX6 R181W mutations failed to transactivate the expression of insulin and genes that encode L-type calcium channel subunits required for normal pancreatic beta-cell function., Conclusions/interpretation: Multidisciplinary and intensive disease management improved the clinical outcomes in four patients with MRS, including adjustment of parenteral/oral nutrition progression and advanced diabetes technologies. A better understanding of RFX6 function, in both intestine and pancreas cells, may break ground in new therapies, particularly regarding the use of drugs that modulate the enteroendocrine system., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2022 Passone, Vermillac, Staels, Besancon, Kariyawasam, Godot, Lambe, Talbotec, Girard, Chardot, Berteloot, Hachem, Lapillonne, Poidvin, Storey, Neve, Stan, Dugelay, Fauret-Amsellem, Capri, Cavé, Ybarra, Chandra, Scharfmann, Bismuth, Polak, Carel, Pigneur and Beltrand.)

Purpose: To evaluate healthcare utilization and satisfaction with treatment before and after implementing direct discharge (DD) from the Emergency Department (ED) of patients with simple, stable musculoskeletal injuries., Methods: Patients with simple, stable musculoskeletal injuries were included in two Dutch hospitals, both level-2 trauma centers: OLVG and Sint Antonius (SA), before (pre-DD-cohort) and after implementing DD (DD-cohort). With DD, no routine follow-up appointments are scheduled after the ED visit, supported by information leaflets, a smartphone application and a telephone helpline. Outcomes included: secondary healthcare utilization (follow-up appointments and X-ray/CT/MRI); satisfaction with treatment (scale 1-10); primary healthcare utilization (general practitioner (GP) or physiotherapist visited, yes/no). Linear regression was used to compare secondary healthcare utilization for all patients and per injury subgroup. Satisfaction and primary healthcare utilization were analyzed descriptively., Results: A total of 2033 (OLVG = 1686; SA = 347) and 1616 (OLVG = 1396; SA = 220) patients were included in the pre-DD-cohort and DD-cohort, respectively. After DD, the mean number of follow-up appointments per patient reduced by 1.06 (1.13-0.99; p < 0.001) in OLVG and 1.07 (1.02-0.93; p < 0.001) in SA. Follow-up appointments reduced significantly for all injury subgroups. Mean number of follow-up X-rays per patient reduced by 0.17 in OLVG (p < 0.001) and 0.18 in SA (p < 0.001). Numbers of CT/MRI scans were low and comparable. In OLVG, mean satisfaction with treatment was 8.1 (pre-DD-cohort) versus 7.95 (DD-cohort), versus 7.75 in SA (DD-cohort only). In OLVG, 23.6% of pre-DD-cohort patients visited their GP, versus 26.1% in the DD-cohort, versus 13.3% in SA (DD-cohort only). Physiotherapist use was comparable., Conclusion: This study performed in a large population and additional hospital confirms earlier pilot results, i.e., that DD has the potential to effectively reduce healthcare utilization, while maintaining high levels of satisfaction., Level of Evidence: II., (© 2021. The Author(s), under exclusive licence to Springer-Verlag GmbH Germany.)

For many parasitic diseases, the microscopic examination of clinical samples such as urine and stool still serves as the diagnostic reference standard, primarily because microscopes are accessible and cost-effective. However, conventional microscopy is laborious, requires highly skilled personnel, and is highly subjective. Requirements for skilled operators, coupled with the cost and maintenance needs of the microscopes, which is hardly done in endemic countries, presents grossly limited access to the diagnosis of parasitic diseases in resource-limited settings. The urgent requirement for the management of tropical diseases such as schistosomiasis, which is now focused on elimination, has underscored the critical need for the creation of access to easy-to-use diagnosis for case detection, community mapping, and surveillance. In this paper, we present a low-cost automated digital microscope-the Schistoscope-which is capable of automatic focusing and scanning regions of interest in prepared microscope slides, and automatic detection of Schistosoma haematobium eggs in captured images. The device was developed using widely accessible distributed manufacturing methods and off-the-shelf components to enable local manufacturability and ease of maintenance. For proof of principle, we created a Schistosoma haematobium egg dataset of over 5000 images captured from spiked and clinical urine samples from field settings and demonstrated the automatic detection of Schistosoma haematobium eggs using a trained deep neural network model. The experiments and results presented in this paper collectively illustrate the robustness, stability, and optical performance of the device, making it suitable for use in the monitoring and evaluation of schistosomiasis control programs in endemic settings.

Purpose: To determine the validity of wrist range of motion (ROM) measurements by the wearable-controlled ReValidate! wrist-rehabilitation game, which simultaneously acts as a digital goniometer. Furthermore, to establish the reliability of the game by contrasting ROM measurements to those found by medical experts using a universal goniometer., Methods: As the universal goniometer is considered the reference standard, inter-rater reliability between surgeons was first determined. Internal validity of the game ROM measurements was determined in a test-retest setting with healthy volunteers. The reliability of the game was tested in 34 patients with a restricted range of motion, in whom the ROM was measured by experts as well as digitally. Intraclass-correlation coefficients (ICCs) were determined and outcomes were analyzed using Bland-Altman plots., Results: Inter-rater reliability between experts using a universal goniometer was poor, with ICCs of 0.002, 0.160 and 0.520. Internal validity testing of the game found ICCs of - 0.693, 0.376 and 0.863, thus ranging from poor to good. Reliability testing of the game compared to medical expert measurements, found that mean differences were small for the flexion-extension arc and the radial deviation-ulnar deviation arc., Conclusion: The ReValidate! game is a reliable home-monitoring device digitally measuring ROM in the wrist. Interestingly, the test-retest reliability of the serious game was found to be considerably higher than the inter-rater reliability of the reference standard, being healthcare professionals using a universal goniometer., Trial Registration Number: (internal hospital registration only) MEC-AMC W17&#95;003 #17.015., (© 2021. The Author(s).)

Objectives: Trauma-induced hemorrhagic shock is characterized by increased endothelial permeability and coagulopathy. Vasopressin analog ddAVP (desmopressin) acts by reorganizing and redistributing adhesive and tight junction molecules, enhancing endothelial barrier function. Furthermore, ddAVP increases von Willebrand factor (vWF) plasma levels and thereby potentially enhances platelet-based coagulation. The objective of this study was to assess whether the use of ddAVP results in improvement of both endothelial barrier function and platelet-based coagulation, thereby improving shock reversal and reduce organ failure in a rat model of trauma and transfusion., Methods: Blood products were prepared from syngeneic rat blood according to blood bank standards. Polytrauma was induced in Sprague Dawley rats by a fractured femur and crush injury to the intestines and liver. The rats were hemorrhaged until a mean arterial pressure of 40 mm Hg and transfused with RBCs, fresh frozen plasmas and platelets in a 1:1:1 ratio, and randomized to receive a single dose of ddAVP (n=7 per group). Blood samples were taken up to 6 hours after trauma to assess biochemistry, markers of endothelial injury and coagulation status by rotational thromboelastometry (ROTEM). Organ damage was assessed by histopathology., Results: Rats receiving ddAVP showed significantly better shock reversal compared with controls. Also, coagulation parameters remained stable in the ddAVP treated group, whereas rats in the control group showed deterioration of coagulation parameters, including decreased clot strength and decreased platelet functioning (89% (IQR 82% to 92%) of baseline values). Platelet count and vWF antigen levels at exsanguination did not differ between groups. ddAVP did not reduce markers of endothelial dysfunction nor markers of organ injury., Conclusions: The use of ddAVP in a rat trauma-transfusion model improved shock parameters and ROTEM parameters of clot formation. However, this did not abrogate the amount of organ failure., Level of Evidence: Level III., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2022. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Fetal and neonatal dysfunctions include rare serious disorders involving abnormal thyroid function during the second half of gestation, which may persist throughout life, as for most congenital thyroid disorders, or be transient, resolving in the first few weeks of life, as in autoimmune hyperthyroidism or hypothyroidism and some cases of congenital hypothyroidism (CH) with the thyroid gland in situ. Primary CH is diagnosed by neonatal screening, which has been implemented for 40 years in developed countries and should be introduced worldwide, as early treatment prevents irreversible neurodevelopmental delay. Central CH is a rarer entity occurring mostly in association with multiple pituitary hormone deficiencies. Other rare disorders impair the action of thyroid hormones. Neonatal Graves' disease (GD) results from the passage of thyrotropin receptor antibodies (TRAbs) across the placenta, from mother to fetus. It may affect the fetuses and neonates of mothers with a history of current or past GD, but hyperthyroidism develops only in those with high levels of stimulatory TRAb activity. The presence of antibodies predominantly blocking thyroid-stimulating hormone receptors may result in transient hypothyroidism, possibly followed by neonatal hyperthyroidism, depending on the balance between the antibodies present. Antithyroid drugs taken by the mother cross the placenta, treating potential fetal hyperthyroidism, but they may also cause transient fetal and neonatal hypothyroidism. Early diagnosis and treatment are key to optimizing the child's prognosis. This review focuses on the diagnosis and management of these patients during the fetal and neonatal periods. It includes the description of a case of fetal and neonatal autoimmune hyperthyroidism., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Premature ovarian insufficiency (POI) is a rare pathology affecting 1-2% of under-40 year-old women, 1 in 1000 under-30 year-olds and 1 in 10,000 under-20 year-olds. There are multiple etiologies, which can be classified as primary (chromosomal, genetic, auto-immune) and secondary or iatrogenic (surgical, or secondary to chemotherapy and/or radiotherapy). Despite important progress in genetics, more than 60% of cases of primary POI still have no identifiable etiology; these cases are known as idiopathic POI. POI is defined by the association of 1 clinical and 1 biological criterion: primary or secondary amenorrhea or spaniomenorrhea of>4 months with onset before 40 year of age, and elevated follicle-stimulating hormone (FSH)>25IU/L on 2 assays at>4 weeks' interval. Estradiol level is low, and anti-Müllerian hormone (AMH) levels have usually collapsed. Initial etiological work-up comprises auto-immune assessment, karyotype, FMR1 premutation screening and gene-panel study. If all of these are normal, the patient and parents may be offered genome-wide analysis under the "France Génomique" project. The term ovarian insufficiency suggests that the dysfunction is not necessarily definitive. In some cases, ovarian function may fluctuate, and spontaneous pregnancy is possible in around 6% of cases. In confirmed POI, hormone replacement therapy is to be recommended at least up to the physiological menopause age of 51 years. Management in a rare diseases center may be proposed., (Copyright © 2021. Published by Elsevier Masson SAS.)

Background: For chronic congenital endocrine conditions, age at diagnosis is a key issue with implications for optimal management and psychological concerns. These conditions are associated with an increase in the risk of comorbid conditions, particularly as  it concerns growth, pubertal development and fertility potential. Clinical presentation and severity depend on the disorder and the patient's age, but diagnosis is often late., Objective: To evaluate age at diagnosis for the most frequent congenital endocrine diseases affecting growth and/or development., Patients and Methods: This observational cohort study included all patients (n = 4379) with well-defined chronic congenital endocrine diseases-non-acquired isolated growth hormone deficiency (IGHD), isolated congenital hypogonadotropic hypogonadism (ICHH), ectopic neurohypophysis (NH), Turner syndrome (TS), McCune-Albright syndrome (MAS), complete androgen insensitivity syndrome (CAIS) and gonadal dysgenesis (GD)-included in the database of a single multisite reference center for rare endocrine growth and developmental disorders, over a period of 14 years. Patients with congenital hypothyroidism and adrenal hyperplasia were excluded as they are generally identified during neonatal screening., Results: Median age at diagnosis depended on the disease: first year of life for GD, before the age of five years for ectopic NH and MAS, 8-10 years for IGHD, TS (11% diagnosed antenatally) and CAIS and 17.4 years for ICHH. One third of the patients were diagnosed before the age of five years. Diagnosis occurred in adulthood in 22% of cases for CAIS, 11.6% for TS, 8.8% for GD, 0.8% for ectopic NH, and 0.4% for IGHD. A male predominance (2/3) was observed for IGHD, ectopic NH, ICHH and GD., Conclusion: The early recognition of growth/developmental failure during childhood is essential, to reduce time-to-diagnosis and improve outcomes., (© 2021. The Author(s).)

Aims: The aim of this study was to investigate whether on-demand removal (ODR) is noninferior to routine removal (RR) of syndesmotic screws regarding functional outcome., Methods: Adult patients (aged above 17 years) with traumatic syndesmotic injury, surgically treated within 14 days of trauma using one or two syndesmotic screws, were eligible (n = 490) for inclusion in this randomized controlled noninferiority trial. A total of 197 patients were randomized for either ODR (retaining the syndesmotic screw unless there were complaints warranting removal) or RR (screw removed at eight to 12 weeks after syndesmotic fixation), of whom 152 completed the study. The primary outcome was functional outcome at 12 months after screw placement, measured by the Olerud-Molander Ankle Score (OMAS)., Results: There were 152 patients included in final analysis (RR = 73; ODR = 79). Of these, 59.2% were male (n = 90), and the mean age was 46.9 years (SD 14.6). Median OMAS at 12 months after syndesmotic fixation was 85 (interquartile range (IQR) 60 to 95) for RR and 80 (IQR 65 to 100) for ODR. The noninferiority test indicated that the observed effect size was significantly within the equivalent bounds of -10 and 10 scale points (p < 0.001) for both the intention-to-treat and per-protocol, meaning that ODR was not inferior to RR. There were significantly more complications in the RR group (12/73) than in the ODR group (1/79) (p = 0.007)., Conclusion: ODR of the syndesmotic screw is not inferior to routine removal when it comes to functional outcome. Combined with the high complication rate of screw removal, this offers a strong argument to adopt on demand removal as standard practice of care after syndesmotic screw fixation. Cite this article: Bone Joint J  2021;103-B(11):1709-1716.

Background: Approximately one-third of musculoskeletal injuries are simple stable injuries (SSIs). Direct discharge (DD) from the emergency department (ED) of patients with SSIs reduces healthcare utilization, without compromising patient outcome and experience, when compared with "traditional" care with routine follow-up. This study aimed to determine the cost-effectiveness of DD compared with traditional care from a societal perspective., Methods: Societal costs, including healthcare, work absenteeism, and travel costs, were calculated for patients with an SSI, 6 months before (pre-DD cohort) and after implementation of DD (DD cohort). The pre-DD cohort was treated according to local protocols. The DD cohort was treated using orthoses, discharge leaflet, smartphone application, and telephone helpline, without scheduling routine follow-up. Effect measures included generic health-related quality of life (HR-QoL; EuroQol Five-Dimensional Questionnaire); disease-specific HR-QoL (functional outcome, different validated questionnaires, converted to 0-100 scale); treatment satisfaction (Visual Analog Scale (VAS), 1-10); and pain (VAS, 1-10). All data were assessed using a 3-month postinjury survey and electronic patient records. Incremental cost-effectiveness ratios were calculated and uncertainty was assessed using bootstrapping techniques., Results: Before DD, 144 of 348 participants completed the survey versus 153 of 371 patients thereafter. There were no statistically significant differences between the pre-DD cohort and the DD cohort for generic HR-QoL (0.03; 95% CI -0.01 to 0.08), disease-specific HR-QoL (4.4; 95% CI -1.1 to 9.9), pain (0.08; 95% CI -0.37 to 0.52) and treatment satisfaction (-0.16; 95% CI -0.53 to 0.21). Total societal costs were lowest in the DD cohort (-€822; 95% CI -€1719 to -€67), including healthcare costs (-€168; 95% CI -€205 to -€131) and absenteeism costs (-€645; 95% CI -€1535 to €100). The probability of DD being cost-effective was 0.98 at a willingness-to-pay of €0 for all effect measures, remaining high with increasing willingness-to-pay for generic HR-QoL, disease-specific HR-QoL, and pain, and decreasing with increasing willingness-to-pay for treatment satisfaction., Discussion: DD from the ED of patients with SSI seems cost-effective from a societal perspective. Future studies should test generalizability in other healthcare systems and strengthen findings in larger injury-specific cohorts., Level of Evidence: II., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Guidelines concerning outpatient management of patients during the coronavirus pandemic required minimized face-to-face follow-up and increased remote care. In response, we established a virtual fracture clinic (VFC) review for emergency department (ED) patients with musculoskeletal injuries, meaning patients are reviewed 'virtually' the next workday by a multidisciplinary team, instead of routine referral for face-to-face fracture clinic review. Patients wait at home and are contacted afterwards to discuss treatment. Based on VFC review, patients with minor injuries are discharged, while for other patients an extensive treatment plan is documented using injury-specific care pathways. Additionally, we established an ED orthopedic trauma fast-track to reduce waiting time. This study aimed to evaluate the extent to which our workflow supported adherence to national coronavirus-related guidelines and effects on ED waiting time., Methods: A closed-loop audit was performed during two 4-week periods using predefined standards: (1) all eligible ED orthopedic trauma patients are referred for VFC review; (2) reached afterwards; and follow-up is (3) patient initiated, or (4) performed remotely, whenever possible. Total ED waiting time, time to review, time for review, and time after review were assessed during both audit periods and compared with previous measurements., Results: During both audits, the majority of eligible ED patients were referred for VFC review (1st: n=162 (88.0%); 2nd: n=302 (98.4%)), and reached afterwards (1st: 98.1%; 2nd: 99.0%). Of all referred patients, 17.9% and 13.6% were discharged 'virtually' during first and second audits, respectively, while 45.0% and 41.1% of scheduled follow-up appointments were remote. Median total ED waiting time was reduced (1st: -36 minutes (p<0.001); 2nd: -33 minutes (p<0.001)). During the second audit, median ED time to review was reduced by -13 minutes (p<0.001), as well as time for review: -10 minutes (p=0.019)., Discussion: In line with national guidelines, our VFC review allowed time-effective review and triage of the majority of ED orthopedic trauma patients, supporting patient-initiated and remote follow-up, whenever possible. ED waiting time was reduced after implementing the VFC review and orthopedic trauma fast-track., Level of Evidence: IV., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Context: Unlike homozygous variants, the implication of heterozygous variants on the leptin-melanocortin pathway in severe obesity has not been established., Objective: To describe the frequency, the phenotype, and the genotype-phenotype relationship for heterozygous variants in LEP, LEPR, POMC, and PCSK1 in severe obesity., Methods: In this retrospective study, genotyping was performed on at least 1 of the LEP, LEPR, POMC, and PCSK1 genes in 1486 probands with severe obesity (600 children, 886 adults). The phenotype was collected in 60 subjects with heterozygous variants and 16 with homozygous variants. We analyzed variant frequency, body mass index (BMI), age of obesity onset, food impulsivity, and endocrine abnormalities., Results: The frequency of subjects with homozygous variants was 1.7% (n = 26), and 6.7% (n = 100) with heterozygous variants. Adults with homozygous variants had a higher BMI (66 vs 53 kg/m2, P = .015), an earlier onset of obesity (0.4 vs 5.4 years, P < .001), more often food impulsivity (83% vs 42%, P = .04), and endocrine abnormalities (75% vs 26%, P < .01). The BMI was higher for subjects with high-impact heterozygous variants (61 vs 50 kg/m², P = .045) and those with a second heterozygous variant on the pathway (65 vs 49 kg/m², P < .01). In children, no significant differences were found for the age of obesity onset and BMI., Conclusion: Heterozygous variants in LEP, LEPR, POMC, and PCSK1 are frequent in severe obesity and sometimes associated with a phenotype close to that of homozygotes. These data suggest a systematic search for variants in severe early-onset obesity, to discuss therapy that targets this key pathway., (© The Author(s) 2021. Published by Oxford University Press on behalf of the Endocrine Society. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Background: In traumatic bleeding, transfusion practice has shifted toward higher doses of platelets and plasma transfusion. The aim of this systematic review was to investigate whether a higher platelet-to-red blood cell (RBC) transfusion ratio improves mortality without worsening organ failure when compared with a lower ratio of platelet-to-RBC., Methods: Pubmed, Medline, and Embase were screened for randomized controlled trials (RCTs) in bleeding trauma patients (age ≥16 years) receiving platelet transfusion between 1946 until October 2020. High platelet:RBC ratio was defined as being the highest ratio within an included study. Primary outcome was 24 hour mortality. Secondary outcomes were 30-day mortality, thromboembolic events, organ failure, and correction of coagulopathy., Results: In total five RCTs (n = 1757 patients) were included. A high platelet:RBC compared with a low platelet:RBC ratio significantly improved 24 hour mortality (odds ratio [OR] 0.69 [0.53-0.89]) and 30- day mortality (OR 0.78 [0.63-0.98]). There was no difference between platelet:RBC ratio groups in thromboembolic events and organ failure. Correction of coagulopathy was reported in five studies, in which platelet dose had no impact on trauma-induced coagulopathy., Conclusions: In traumatic bleeding, a high platelet:RBC improves mortality as compared to low platelet:RBC ratio. The high platelet:RBC ratio does not influence thromboembolic or organ failure event rates., (© 2021 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

Background: The optimal treatment of isolated displaced partial articular radial head fractures remains controversial. The aim of this randomized controlled trial was to compare the functional outcome of operative treatment with nonoperative treatment in adults with an isolated Mason type 2 radial head fractures., Methods: In this multicenter randomized controlled trial, patients from 18 years of age with an isolated partial articular fracture of the radial head were randomly assigned to operative treatment by means of open reduction and screw fixation or nonoperative treatment with a pressure bandage. The primary outcome was function assessed with the Disabilities of the Arm, Shoulder, and Hand (DASH) questionnaire. Questionnaires and clinical follow-up was conducted at admission and at 3, 6, and 12 months., Results: In total, 45 patients were randomized, 23 patients to open reduction and screw fixation and 22 patients to nonoperative treatment with a pressure bandage. At 3, 6, and 12 months, patients treated operatively had similar functional outcomes compared to patients treated nonoperatively (DASH score at 12 months: 0.0 [0.0-4.2] vs. 1.7 [0.0-8.5]; P = .076)., Conclusions: Nonoperatively treated adults with an isolated Mason type 2 radial head fracture have similar functional results after 1 year compared with operatively treated patients. In addition, complication rates were low for both operative and nonoperative treatment., (Copyright © 2021 The Authors. Published by Elsevier Inc. All rights reserved.)

Purpose: Cervical spine injury after blunt trauma in children is rare but can have severe consequences. Clear protocols for diagnostic workup are, therefore, needed, but currently not available. As a step in developing such a protocol, we determined the incidence of cervical spine injury and the degree of protocol adherence at our level 2 trauma centre., Methods: We analysed data from all patients aged < 16 years suspected of cervical spine injury after blunt trauma who had presented to our hospital during two periods: January 2010 to June 2012, and January 2017 to June 2019. In the intervening period, the imaging protocol for diagnostic workup was updated. Outcomes were the incidence of cervical spine injury and protocol adherence in terms of the indication for imaging and the type of imaging., Results: We included 170 children in the first study period and 83 in the second. One patient was diagnosed with cervical spine injury. Protocol adherence regarding the indication for imaging was > 80% in both periods. Adherence regarding the imaging type decreased over time, with 45.8% of the patients receiving a primary CT scan in the second study period versus 2.9% in the first., Conclusion: Radiographic imaging is frequently performed when clearing the paediatric cervical spine, although cervical spine injury is rare. Particularly CT scan usage has wrongly been emerging over time. Stricter adherence to current protocols could limit overuse of radiographic imaging, but ultimately there is a need for an accurate rule predicting which children really are at risk of injury.

Background: Recent studies suggest a large proportion of musculoskeletal injuries are simple stable injuries (SSIs). The aim of this study was to evaluate whether direct discharge (DD) from the emergency department (ED) of SSIs is non-inferior to 'traditional care' regarding treatment satisfaction and functional outcome, and to compare other patient-reported outcomes (PROMs), patient-reported experiences (PREMs), resource utilization, and adverse outcomes before and after DD., Methods: This trial compared outcomes for 11 SSIs 6 months before and after the implementation of DD protocols. Pre-DD, patients were treated according to local protocols. Post-DD, patients were discharged directly using removable orthoses, discharge leaflets, smartphone application, and telephone helpline. Participants received a 3-month postinjury PROM/PREM survey to assess treatment satisfaction (Visual Analog Scale, VAS), pain (VAS), functional outcome (four validated questionnaires), and health-related quality of life (HR-QoL; EuroQol-5D). Resource utilization included general practitioner (GP) visit (yes/no), physiotherapist visit (yes/no), return to work/school/sports (days), work/school absenteeism to visit hospital (yes/no), number of hospital visits, and follow-up X-rays. Other outcomes included missed injuries (additionally to SSI) and adverse outcomes (delayed union, non-union). Between-group differences were assessed using propensity score-adjusted regression analyses. Non-inferiority was assessed for satisfaction and functional outcome using predefined margins., Results: 348 (pre-DD) and 371 (post-DD) patients participated; 144 (41.4%) and 153 (41.2%) patients completed the survey. Satisfaction and functional outcome post-DD were non-inferior to traditional care. Mean satisfaction was 8.13 pre-DD and 7.95 post-DD (mean difference: -0.16, p=0.408). Pain, HR-QoL, GP/physiotherapist visits, and return to work/school/sports were comparable before and after DD. Work absenteeism was higher pre-DD (OR 0.110, p<0.001), as well as school absenteeism (OR 0.084, p<0.001). Post-DD, the mean number of hospital visits and X-rays reduced: -1.68 (p<0.001) and -0.26 (p<0.001). Missed injuries occurred once pre-DD versus twice post-DD. There were no adverse outcomes., Discussion: The results of this study confirm several SSIs can be discharged directly from the ED without compromising patient outcome/experience. Future injury-specific trials are needed to conclusively assess non-inferiority of DD., Level of Evidence: II., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY-NC. No commercial re-use. See rights and permissions. Published by BMJ.)

Objective: SRY-negative 46,XX testicular and ovotesticular disorders/differences of sex development (T/OTDSD) represent a very rare and unique DSD condition where testicular tissue develops in the absence of a Y chromosome. To date, very few studies have described the phenotype, clinical and surgical management and long-term outcomes of these patients. Particularly, early blockade of the gonadotropic axis in patients raised in the female gender to minimize postnatal androgenization has never been reported., Design: Retrospective description of sixteen 46,XX T/OTDSD patients., Results: Sixteen 46,XX SRY-negative T/OTDSD were included. Most (12/16) were diagnosed in the neonatal period. Sex of rearing was male for six patients and female for ten, while the clinical presentation varied, with an external masculinization score from 1 to 10. Five patients raised as girl were successfully treated with GnRH analog to avoid virilization during minipuberty. Ovotestes/testes were found bilaterally for 54% of the patients and unilaterally for the others (with a contralateral ovary). Gonadal surgery preserved appropriate tissue in the majority of cases. Spontaneous puberty occurred in two girls and one boy, while two boys required hormonal induction of puberty. One of the girls conceived spontaneously and had an uneventful pregnancy. DNA analyses (SNP-array, next-generation sequencing and whole-exome sequencing) were performed. A heterozygous frameshit mutation in the NR2F2 gene was identified in one patient., Conclusions: This study presents a population of patients with 46,XX SRY-negative T/OTDSD. Early blockade of gonadotropic axis appears efficient to reduce and avoid further androgenization in patients raised as girls., (© 2020 John Wiley & Sons Ltd.)

Objectives: To investigate the incidence of surgical site infections (SSIs) after routine removal of syndesmotic screws (SSs) placed to stabilize syndesmotic injuries., Data Sources: A systematic literature search was performed in the PubMed, Cochrane, and EMBASE databases for studies published online before February 2020, using the key words and synonyms of "syndesmotic screw" ("ankle fractures" or "syndesmotic injury") and "implant removal.", Study Selection: Studies were eligible for inclusion when they described >10 adult patients undergoing elective/scheduled removal of the SS., Data Extraction: The 15 included articles were assessed for quality and risk of bias using the Newcastle-Ottawa Scale. Baseline characteristics of the studies, the study population, the intervention, the potential confounders, and the primary outcome (% of SSIs) were extracted using a customized extraction sheet., Data Synthesis: The primary outcome was presented as a proportion of included patients and as a weighted mean, using inverse variance, calculated in RStudio. Furthermore, potential confounders were identified., Conclusions: The percentage of SSIs ranged from 0% to 9.2%, with a weighted mean of 4%. The largest proportion of these infections were superficial (3%, 95% confidence interval: 2-5), compared with 2% deep infections (95% confidence interval: 1-4). These rates were comparable to those of other foot/ankle procedures indicating that the individual indication for SS removal (SSR) should be carefully considered. Future studies should focus on valid indications for SSR, the influence of prophylactic antibiotics on an SSI after SSR, and complications of retaining the SS to enable a fair benefits/risks comparison of routine versus on-demand removal of the SS., Level of Evidence: Therapeutic Level III. See Instructions for Authors for a complete description of levels of evidence., Competing Interests: The authors report no conflict of interest., (Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.)

Introduction: Distal radius fractures are among the most prevalent traumatic injuries worldwide. These injuries are associated with high healthcare-related and socioeconomic costs, mainly resulting from loss of productivity. To optimise recovery and return to work, wrist exercises are recommended. However, adherence to standard exercise regimens is low. Serious games provide a treatment platform for standardised postoperative care, uniting meaningful recovery with entertainment. Also, mobile serious games, for example, smartphone or tablet applications, are able to send practice reminders believed to improve self-efficacy., Methods and Analysis: To test the effectiveness of a mobile serious game for distal radius fracture rehabilitation compared with standard care, a multicentre, randomised controlled clinical trial was designed. Primary outcome will be the Patient-Rated Wrist Evaluation (PRWE) score after 6 weeks of treatment. Secondary outcomes are range of motion, grip strength, pain scores, and self-reported treatment adherence after 2, 6 and 12 weeks of treatment.Adult patients with any type of closed distal radius fracture are included directly after non-operative or operative fracture treatment. Patients are recruited in the outpatient clinics of four teaching hospitals. The intended sample size is 92 patients, based on the minimal clinically important difference of the PRWE score at 6 weeks, using a superiority model.Patients are randomised between using the wearable-controlled mobile serious game ReValidate! (intervention group) and standard care consisting of unsupervised exercises and a referral for physiotherapy or exercise therapy upon request or recommendation by the treating clinician (control group)., Ethics and Dissemination: The protocol has been approved by the Medical Ethical Review Board of the Amsterdam University Medical Centres, location Academic Medical Centre in Amsterdam, the Netherlands. Results will be made available to involved healthcare providers, funders, and to the general public including patients via peer-reviewed academic journals and international conferences., Trial Registration Number: Dutch Trial Registry (NTR), NL6140, protocol V.2., Competing Interests: Competing interests: None declared., (© Author(s) (or their employer(s)) 2021. Re-use permitted under CC BY. Published by BMJ.)

Objective: Neonatal hyperthyroidism may be caused by a permanent non-autoimmune genetic disorder or, more frequently, by maternally transmitted high serum TRAb levels. Variable thyroid dysfunction may be observed in this second context. We aimed to evaluate the prevalence of neonatal non-autoimmune hyperthyroidism and of the different types of thyroid function in neonates with a high risk of hyperthyroidism due to maternal Graves' disease (GD)., Design and Methods: This observational cohort study included all neonates identified in the database of a single academic pediatric care center, over a period of 13 years, as having non-autoimmune hyperthyroidism or an autoimmune disorder with high TRAb levels (above 6 IU/L) transmitted by their mothers. Patients were classified as having neonatal hyperthyroidism, hypothyroidism, or euthyroidism with a permanent or transient disorder., Results: Two of the 34 consecutive neonates selected (6%) had permanent non-autoimmune hyperthyroidism due to germline (n = 1) or somatic (n = 1) mutations of the TSH receptor gene. The patients with high serum TRAb levels at birth had transient hyperthyroidism (n = 23), hypothyroidism (primary n = 2, central n = 3) or persistent euthyroidism (n = 4)., Conclusion: These original findings highlight the need for careful and appropriate monitoring of thyroid function in the long term, not only for the rare patients with non-autoimmune neonatal hyperthyroidism, but also for repeat monitoring during the first month of life in neonates with maternally transmitted high TRAb levels, to ensure the early identification of thyrotoxicosis in more than two thirds of cases and to detect primary or central hypothyroidism, thereby potentially decreasing associated morbidity.

The control and elimination of schistosomiasis have over the last two decades involved several strategies, with the current strategy by the World Health Organization (WHO) focusing mainly on treatment with praziquantel during mass drug administration (MDA). However, the disease context is complex with an interplay of social, economic, political, and cultural factors that may affect achieving the goals of the Neglected Tropical Disease (NTD) 2021-2030 Roadmap. There is a need to revisit the current top-down and reactive approach to schistosomiasis control among sub-Saharan African countries and advocate for a dynamic and diversified approach. This paper highlights the challenges of praziquantel-focused policy for schistosomiasis control and new ways to move from schistosomiasis control to elimination in sub-Saharan Africa. We will also discuss an alternative and diversified approach that consists of a Systems Thinking Framework that embraces intersectoral collaboration fully and includes co-creating locally relevant strategies with affected communities. We propose that achieving the goals for control and elimination of schistosomiasis requires a bottom-up and pro-active approach involving multiple stakeholders. Such a pro-active integrated approach will pave the way for achieving the goals of the NTD 2021-2030 roadmap for schistosomiasis, and ultimately improve the wellbeing of those living in endemic areas., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Onasanya, Bengtson, Oladepo, Van Engelen and Diehl.)

Background: Interstitial lung disease (ILD) corresponds to a heterogeneous group of pathologies that differ in etiology with common clinical and radiological manifestations. In Latin America and Mexico, reports are scarce and the need for studies to understand the scenario is emphasized., Objective: To analyze a multidimensional profile in patients with interstitial lung disease in Yucatan., Method: This is an observational, prospective, analytic, descriptive study including consecutive patients diagnosed with ILD over a 4-year period. Demographic and clinical data, lung function tests, chest imaging, serum immunological profile, and echocardiographic findings were recorded. Differences between subgroups were analyzed performing a one-way analysis of variance (ANOVA)., Results: 110 patients were included. The median age was 60 years and women were most affected. The main cause of ILD was related with connective tissue diseases (CTD). A group subanalysis revealed that Idiopathic pulmonary fibrosis (IPF) was common in males with a history of smoking and an imaging pattern of usual interstitial pneumonia. Lung function tests showed a moderate-to-severe pulmonary restriction (FVC 55%p) and mild hypoxemia (PaO2 79mmHg). Positive antinuclear antibodies are less likely in cases with IPF (20 vs. 65%; p = 0.006)., Conclusion: In Southeastern Mexico, ILD occurs in women in their seventh decade of life; the most common cause is related with CTD. Our results support that ILD has a heterogeneous expression and is relevant the need for subsequent studies characterizing each ILD.

Objective: Isolated central precocious puberty (CPP) includes sporadic, familial and adoption-related forms, and the characterization of its etiology is challenging. This study investigated the prevalence and clinical characteristics of isolated CPP., Design and Methods: This observational cohort study included all patients (n = 395) with CPP included in the database of a single academic pediatric care center over a period of 11.5 years., Results: In total, 332 of the 395 patients (84%) had isolated forms of CPP; the proportion of male patients was lower in this group than for non-isolated CPP (4 vs 33%, P < 0.0001). These patients had sporadic (n = 228, 68.5%), familial (n = 82, 25%) or adoption-related (n = 22, 6.5%) forms. Clinical characteristics at diagnosis were similar between groups, but girls with sporadic CPP were older at referral than those with familial or adoption-related CPP (P < 0.02), and birth weight SDS was lower in adopted patients than in those from the sporadic and familial groups (P < 0.01). In the 72 families containing patients with familial forms, both recessive and dominant transmissions were observed between first-degree relatives. Potential maternal or paternal transmission was identified in two-thirds of the studied families, in similar proportions. An autosomal dominant mode of transmission with low penetrance was suggested by the high proportion of affected parents (33 of the 72 families, 46%). Clinical presentation was similar whatever the mode of inheritance., Conclusion: These findings highlight the need for careful monitoring of the various forms of CPP. Future studies should explore pathophysiological mechanisms, particularly for familial forms.

Background: Elective implant removal (IR) after fracture fixation is one of the most common procedures within (orthopedic) trauma surgery. The rate of surgical site infections (SSIs) in this procedure is quite high, especially below the level of the knee. Antibiotic prophylaxis is not routinely prescribed, even though it has proved to lower SSI rates in other (orthopedic) trauma surgical procedures. The primary objective is to study the effectiveness of a single intravenous dose of 2 g of cefazolin on SSIs after IR following fixation of foot, ankle and/or lower leg fractures., Methods: This is a multicenter, double-blind placebo controlled trial with a superiority design, including adult patients undergoing elective implant removal after fixation of a fracture of foot, ankle, lower leg or patella. Exclusion criteria are: an active infection, current antibiotic treatment, or a medical condition contraindicating prophylaxis with cefazolin including allergy. Patients are randomized to receive a single preoperative intravenous dose of either 2 g of cefazolin or a placebo (NaCl). The primary analysis will be an intention-to-treat comparison of the proportion of patients with a SSI at 90 days after IR in both groups., Discussion: If 2 g of prophylactic cefazolin proves to be both effective and cost-effective in preventing SSI, this would have implications for current guidelines. Combined with the high infection rate of IR which previous studies have shown, it would be sufficiently substantiated for guidelines to suggest protocolled use of prophylactic antibiotics in IR of foot, ankle, lower leg or patella. Trial registration Nederlands Trial Register (NTR): NL8284, registered on 9th of January 2020, https://www.trialregister.nl/trial/8284.

Significance: Particle field holography is a versatile technique to determine the size and distribution of moving or stationary particles in air or in a liquid without significant disturbance of the sample volume. Although this technique is applied in biological sample analysis, it is limited to small sample volumes, thus increasing the number of measurements per sample. In this work, we characterize the maximum achievable volume limit based on the specification of a given sensor to realize the development of a potentially low-cost, single-shot, large-volume holographic microscope., Aim: We present mathematical formulas that will aid in the design and development and improve the focusing speed for the numerical reconstruction of registered holograms in particle field holographic microscopes. Our proposed methodology has potential application in the detection of Schistosoma haematobium eggs in human urine samples., Approach: Using the Fraunhofer holography theory for opaque objects, we derived an exact formula for the maximum diffraction-limited volume for an in-line holographic setup. The proof-of-concept device built based on the derived formulas was experimentally validated with urine spiked with cultured Schistosoma haematobium eggs., Results: Results obtained show that for urine spiked with Schistosoma haematobium eggs, the volume thickness is limited to several millimeters due to scattering properties of the sample. The distances of the target particles could be estimated directly from the hologram fringes., Conclusion: The methodology proposed will aid in the development of large-volume holographic microscopes.

Introduction: In hemorrhaging trauma patients, the endothelium is activated, resulting in excessive endothelial synthesis of von Willebrand Factor (vWF), which may enhance micro-thrombi formation, resulting in obstruction of the microcirculation and endothelial injury, aggravating bleeding, as well as contributing to organ failure. Under normal conditions, vWF is cleaved by the metalloprotease ADAMTS-13. After trauma, ADAMTS-13 levels are reduced., Objectives: To assess whether recombinant human ADAMTS-13 inhibits endothelial injury and organ failure in a rat trauma-transfusion model., Methods: Blood products were prepared from syngeneic rat blood according to blood bank standards. Polytrauma was induced in rats by crush injury to the intestines and liver and by fracture of the femur. The rats were hemorrhaged until a mean arterial pressure (MAP) of 40 mmHg was reached. Rats were randomized to receive transfusion of RBCs, FFPs, and platelets in a 1:1:1 ratio to achieve a MAP of 70 mmHg, with or without the addition of ADAMTS-13 (50 μg/kg). Blood samples were assessed for biochemistry and rotational thromboelastometry (ROTEM). Syndecan-1 and VE-cadherin levels were measured as a reflection of endothelial integrity. The amount of leakage of dextran-FITC from the vascular system to the parenchyma in lungs was quantified. To assess inflammation, IL-6 and IL-8 levels were determined. Organ damage was assessed by histopathology., Results: All rats were severely shocked, with no significant differences in shock parameters between groups. Rats treated with ADAMTS-13 showed signs of a more effective shock reversal (higher blood pressure, lower lactate levels) compared to controls. Also, ROTEM parameters of clot formation in rats receiving ADAMTS-13 improved compared to controls, which was mainly platelet-dependent. Syndecan-1 levels relative to baseline trended to be lower in ADAMTS-13 treated rats compared to controls (107 vs 149%, p = 0.08). ADAMTS-13 reduced albuminuria (1.7 vs 4.4 g/L, p < 0.01) and organ-specific inflammation (pulmonary IL-6 243 vs 369 pg/mL, p = 0.08; splenic IL-6 253 vs 307, p = 0.03) compared to controls, but did not improve histopathological scores., Conclusions: The use of ADAMTS-13 in a rat trauma-transfusion model improves parameters of shock, platelet-driven coagulation, endothelial damage, and organ inflammation. These results suggest that ADAMTS-13 is important in mediating outcome of trauma. Whether ADAMTS-13 can be used as a therapeutic adjunct to treat bleeding trauma patients remains to be determined.

Objective: To evaluate the safety of implementing the Amsterdam Wrist Rules (AWR) during Emergency Department (ED) nurse triage, and to assess the potential reduction of radiographic images., Design: Prospective cohort study METHODS: Based on patient characteristics and clinical variables the AWR-application advised triage nurses if radiographic imaging was necessary of patients (>3 years) presenting with trauma of the wrist. The triage nurse was allowed to perform radiographic imaging if the advice was negative. Safety was assessed by the number of missed clinically relevant distal radius fractures (DRFs) when the AWR advised not to perform imaging. The potential reduction of radiographic images was assessed by the proportion of patients in whom the AWR-application advised not to perform imaging. Compliance was defined as following this advice. Patient satisfaction was assessed if no radiographic imaging was performed., Results: The AWR-application advised not to perform imaging in 18% of children (n=153) and in 9% of adults (n=204). In children, one clinically relevant DRF was missed (sensitivity 99%, specificity 33%) and none in adults (sensitivity 100%, specificity 19%). The compliance was 22% in children and 32% in adults. If no radiographic imaging was performed, 100% of children and 75% of adults were satisfied., Conclusion: Implementation of the AWR during ED nurse triage of patients presenting with wrist trauma can safely contribute to reducing unnecessary radiographic imaging. If other injuries than a clinically relevant DRF are suspected based on triage, an ED physician should decide if imaging is necessary.

Purpose: Nosocomial infection contributes to adverse outcome after brain injury. This study investigates whether autonomic nervous system activity is associated with a decreased host immune response in patients following stroke or traumatic brain injury (TBI)., Methods: A prospective study was performed in adult patients with TBI or stroke who were admitted to the Intensive Care Unit of our tertiary university hospital between 2013 and 2016. Heart rate variability (HRV) was recorded daily and assessed for autonomic nervous system activity. Outcomes were nosocomial infections and immunosuppression, which was assessed ex vivo using whole blood stimulations with plasma of patients with infections, matched non-infected patients and healthy controls., Results: Out of 64 brain injured patients, 23 (36%) developed an infection during their hospital stay. The ability of brain injured patients to generate a host response to the bacterial endotoxin lipopolysaccharides (LPS) was diminished compared to healthy controls (p < 0.001). Patients who developed an infection yielded significantly lower TNF-α values (86 vs 192 pg/mL, p = 0.030) and a trend towards higher IL-10 values (122 vs 84 pg/mL, p = 0.071) following ex vivo whole blood stimulations when compared to patients not developing an infection. This decreased host immune response was associated with altered admission HRV values. Brain injured patients who developed an infection showed increased normalized high-frequency power compared to patients not developing an infection (0.54 vs 0.36, p = 0.033), whereas normalized low-frequency power was lower in infected patients (0.46 vs 0.64, p = 0.033)., Conclusion: Brain injured patients developing a nosocomial infection show parasympathetic predominance in the acute phase following brain injury, reflected by alterations in HRV, which parallels a decreased ability to generate an immune response to stimulation with LPS.

Background: Schistosomiasis, one of the neglected tropical diseases, is a water-based parasitic disease of public health importance. Currently, tests for Schistosoma haematobium infection either demonstrate poor specificity, are expensive or too laborious for use in endemic countries, creating a need for more sensitive, cheaper, and easy to use devices for the diagnosis of schistosomiasis. To ensure engagement during the process of device development; and effective acceptance and use after the introduction of diagnostics devices for S. haematobium , there is a need to involve stakeholders with varying power, interest, and stakes in device co-creation, as well as those relevant for later use situation in the diagnostic landscape. The main goal of this study is to identify and analyze relevant stakeholders for co-creation using a power-interest matrix. Materials and Methods: The study was based on an action research methodology using a case study approach. A contextual inquiry approach consisting of 2 stages: stakeholder identification and interview; and stakeholder analysis was used. The field part of the study was carried out in Oyo State, Nigeria using a multistage cluster purposive sampling technique based on the category of stakeholders to be interviewed predicated on the organizational structure within the state and communities. A mix of qualitative research techniques was used. Identified themes related to power and interest were mapped and analyzed. Results: We identified 17 characteristics of stakeholders across 7 categories of stakeholders important for schistosomiasis diagnostics. Most of the stakeholders were important for both the co-creation and adoption phase of the device development for diagnostics. However, not all stakeholders were relevant to co-creation. Key Stakeholders relevant for diagnostics co-creation demonstrated significant social power, organization power, and legitimate power bases. Most of the stakeholders showed significant interest in the device to be created. Discussion: The power and interest of these stakeholders reveal some insight into how each stakeholder may be engaged for both co-creation and device usage. The involvement of relevant actors who will also be important for co-creation and implementation, will simplify the engagement process for the critical stakeholders, increase the ability to manage the process, and increase diagnostic device acceptability., (Copyright © 2020 Onasanya, Keshinro, Oladepo, Van Engelen and Diehl.)

The rapid growth of point-of-care (POC) diagnostic tests necessitates a clear vision of when, where, and why a new POC diagnostic test needs to be developed and how it can be used in a way that matches a local health care context. Here, we present an innovative approach toward developing a concept target product profile (CTPP), which is a new mapping tool that helps researchers match a new diagnostic test to a specific local health care context early in the research and development process. As a case study, we focus on the diagnosis of visceral leishmaniasis (VL) in rural resource-limited regions of Kenya and Uganda. Our stepwise approach integrates elements of design thinking and uses a combination of literature reviews and field research for a context analysis of local health care systems and practices. We then use visual thinking in the form of Gigamaps and patient journeys to identify use case scenarios and to present our findings from the field research to key stakeholders. The use case scenarios describe the diagnostic scope of a new POC test based on the feasibility of the new test, the local need, and the contextual fit. For our case study of VL, we identify 2 valuable use case scenarios, namely test-of-cure and screening and confirmation, and we formulate a CTPP. We anticipate that a CTPP will enable researchers to match a new POC diagnostic test during the research and development process to the local health care context in which it will be used., (© Bengtson et al.)

Aims/hypothesis: Low-dose IL-2 (ld-IL2) selectively activates and expands regulatory T cells (Tregs) and thus has the potential to skew the regulatory/effector T (Treg/Teff) cell balance towards improved regulation. We investigated which low doses of IL-2 would more effectively and safely activate Tregs during a 1 year treatment in children with recently diagnosed type 1 diabetes., Methods: Dose Finding Study of IL-2 at Ultra-low Dose in Children With Recently Diagnosed Type 1 Diabetes (DF-IL2-Child) was a multicentre, double-blinded, placebo-controlled, dose-finding Phase I/II clinical trial conducted in four centres at university hospitals in France: 24 children (7-14 years old) with type 1 diabetes diagnosed within the previous 3 months were randomly assigned 1:1:1:1 to treatment by a centralised randomisation system, leading to a 7/5/6/6 patient distribution of placebo or IL-2 at doses of 0.125, 0.250 or 0.500 million international units (MIU)/m 2 , given daily for a 5 day course and then fortnightly for 1 year. A study number was attributed to patients by an investigator unaware of the randomisation list and all participants as well as investigators and staff involved in the study conduct and analyses were blinded to treatments. The primary outcome was change in Tregs, expressed as a percentage of CD4 + T cells at day 5. It pre-specified that a ≥60% increase in Tregs from baseline would identify Treg high responders., Results: There were no serious adverse events. Non-serious adverse events (NSAEs) were transient and mild to moderate. In treated patients vs placebo, the commonest NSAE was injection site reaction (37.9% vs 3.4%), whereas other NSAEs were at the same level (23.3% vs 19.2%). ld-IL2 induced a dose-dependent increase in the mean proportion of Tregs, from 23.9% (95% CI -11.8, 59.6) at the lowest to 77.2% (44.7, 109.8) at the highest dose, which was significantly different from placebo for all dose groups. However, the individual Treg responses to IL-2 were variable and fluctuated over time. Seven patients, all among those treated with the 0.250 and 0.500 MIU m -2  day -1 doses, were Treg high responders. At baseline, they had lower Treg proportions in CD4 + cells than Treg low responders, and serum soluble IL-2 receptor α (sIL-2RA) and vascular endothelial growth factor receptor 2 (VEGFR2) levels predicted the Treg response after the 5 day course. There was no significant change in glycaemic control in any of the dose groups compared with placebo. However, there was an improved maintenance of induced C-peptide production at 1 year in the seven Treg high responders as compared with low responders., Conclusions/interpretation: The safety profile at all doses, the dose-dependent effects on Tregs and the observed variability of the Treg response to ld-IL2 in children with newly diagnosed type 1 diabetes call for use of the highest dose in future developments. The better preservation of insulin production in Treg high responders supports the potential of Tregs in regulating autoimmunity in type 1 diabetes, and warrants pursuing the investigation of ld-IL2 for its treatment and prevention., Trial Registration: ClinicalTrials.gov NCT01862120., Funding: Assistance Publique-Hôpitaux de Paris, Investissements d'Avenir programme (ANR-11-IDEX-0004-02, LabEx Transimmunom and ANR-16-RHUS-0001, RHU iMAP) and European Research Council Advanced Grant (FP7-IDEAS-ERC-322856, TRiPoD).

Aims: The primary aim of this study was to address the hypothesis that fracture morphology might be more important than posterior malleolar fragment size in rotational type posterior malleolar ankle fractures (PMAFs). The secondary aim was to identify clinically important predictors of outcome for each respective PMAF-type, to challenge the current dogma that surgical decision-making should be based on fragment size., Methods: This observational prospective cohort study included 70 patients with operatively treated rotational type PMAFs, respectively: 23 Haraguchi Type I (large posterolateral-oblique), 22 Type II (two-part posterolateral and posteromedial), and 25 (avulsion-) Type III. There was no standardized protocol on how to address the PMAFs and CT-imaging was used to classify fracture morphology and quality of postoperative syndesmotic reduction. Quantitative 3D-CT (Q3DCT) was used to assess the quality of fracture reduction, respectively: the proportion of articular involvement; residual intra-articular: gap, step-off, and 3D-displacement; and residual gap and step-off at the fibular notch. These predictors were correlated with the Foot and Ankle Outcome Score (FAOS) at two-years follow-up., Results: Bivariate analyses revealed that fracture morphology (p = 0.039) as well as fragment size (p = 0.007) were significantly associated with the FAOS. However, in multivariate analyses, fracture morphology (p = 0.001) (but not fragment size (p = 0.432)) and the residual intra-articular gap(s) (p = 0.009) were significantly associated. Haraguchi Type-II PMAFs had poorer FAOS scores compared with Types I and III. Multivariate analyses identified the following independent predictors: step-off in Type I; none of the Q3DCT-measurements in Type II, and quality of syndesmotic reduction in small-avulsion Type III PMAFs., Conclusion: PMAFs are three separate entities based on fracture morphology, with different predictors of outcome for each PMAF type. The current debate on whether or not to fix PMAFs needs to be refined to determine which morphological subtype benefits from fixation. In PMAFs, fracture morphology should guide treatment instead of fragment size. Cite this article: Bone Joint J 2020;102-B(9):1229-1241.

Introduction: Transfusion therapy in hemorrhaging trauma patients is associated with the development of thromboembolic events. It is unknown whether current resuscitation strategies, including large volumes of plasma and early administration of procoagulant therapy, increases this risk., Methods: A systematic search was conducted in MEDLINE, PubMed, and Embase. Studies were screened by two independent reviewers and included if they reported on thromboembolic events in patients with severe trauma (injury severity score ≥16) who received transfusion of at least 1 unit of red blood cells. The ratio by which blood products were transfused, as well as use of procoagulant or antifibrinolytic medication, was recorded., Results: A total of 40 studies with 11.074 bleeding trauma patients were included, in which 1.145 thromboembolic events were reported, yielding an incidence of 10% thromboembolic events. In studies performing routine screening for thromboembolic complications, the incidence ranged from 12% to 23%. The risk of thromboembolic events was increased after administration of tranexamic acid (TXA; odds ratio [OR], 2.6; 95% confidence interval [CI], 1.7-4.1; p < 0.001) and fibrinogen concentrate (OR, 2.1; 95% CI, 1.0-4.2; p = 0.04). Blood product ratio, the use of prothrombin complex concentrate or recombinant factor VIIa were not associated with thromboembolic events., Conclusion: This systematic review identified an incidence of thromboembolic events of 10% in severely injured bleeding trauma patients. The use of TXA and fibrinogen concentrate was associated with the development of thromboembolic complications., (© 2020 The Authors. Transfusion published by Wiley Periodicals LLC. on behalf of AABB.)

Background: Recombinant human growth hormone has been used for more than 30 years and its indications have increased worldwide. There is concern that this treatment might increase mortality, but published data are scarce. We present data from the entire dataset of all eight countries of the Safety and Appropriateness of Growth hormone treatments in Europe (SAGhE) consortium, with the aim of studying long-term overall and cause-specific mortality in young adult patients treated with recombinant human growth hormone during childhood and relating this to the underlying diagnosis., Methods: This cohort study was done in eight European countries (Belgium, France, Germany, Italy, The Netherlands, Sweden, Switzerland, and the UK). Patients were classified a priori based on pre-treatment perceived mortality risk from their underlying disease and followed up for cause-specific mortality. Person-years at risk of mortality and expected rates from general population data were used to calculate standardised mortality ratios (SMRs)., Findings: The cohort comprised 24 232 patients treated with recombinant human growth hormone during childhood, with more than 400 000 patient-years of follow-up. In low-risk patients with isolated growth hormone deficiency or idiopathic short stature, all-cause mortality was not significantly increased (SMR 1·1, 95% CI 0·9-1·3). In children born small for gestational age, all-cause mortality was significantly increased when analysed for all countries (SMR 1·5, CI 1·1-1·9), but this result was driven by the French subcohort. In patients at moderate or high risk, mortality was increased (SMR 3·8, 3·3-4·4; and 17·1, 15·6-18·7, respectively). Mortality was not associated with mean daily or cumulative doses of recombinant human growth hormone for any of the risk groups. Cause-specific mortality from diseases of the circulatory and haematological systems was increased in all risk groups., Interpretation: In this cohort, the largest, to our knowledge, with long-term follow-up of patients treated with recombinant human growth hormone during childhood, all-cause mortality was associated with underlying diagnosis. In patients with isolated growth hormone deficiency or idiopathic short stature, recombinant human growth hormone treatment was not associated with increased all-cause mortality. However, mortality from certain causes was increased, emphasising the need for further long-term surveillance., Funding: European Union., (Copyright © 2020 Elsevier Ltd. All rights reserved.)

Background: Three-dimensional (3D) fluoroscopy is thought to be advantageous in the open reduction and internal fixation (ORIF) of calcaneal fractures. The goal of this multicenter randomized controlled trial was to investigate the clinical effect of additional intraoperative 3D fluoroscopy on postoperative quality of reduction and fixation and patient-reported outcome as compared to conventional 2-dimensional (2D) fluoroscopy in patients with intra-articular fractures of the calcaneus., Methods: Patients were randomized to 3D or conventional 2D fluoroscopy during operative treatment of calcaneal fractures. Primary outcome was the difference in quality of fracture reduction and implant position on postoperative computed tomography (CT). Secondary endpoints included intraoperative corrections (prior to wound closure), complications, and revision surgery (after wound closure). Function and patient-reported outcome were evaluated after surgery and included range of motion, Foot and Ankle Outcome Score (FAOS), American Orthopaedic Foot & Ankle Society (AOFAS) score, Short-Form 36 (SF-36) questionnaires, and Kellgren-Lawrence posttraumatic osteoarthritis classification. A total of 102 calcaneal fractures were included in the study in 100 patients. Fifty fractures were randomized to the 3D group and 52 to the 2D group., Results: There was a statistically significant difference in duration of surgery between the groups (2D 125 min vs 3D 147 min; P < .001). After 3D fluoroscopy, a total of 57 intraoperative corrections were performed in 28 patients (56%). The postoperative CT scan revealed an indication for additional revision of reduction or implant position in 69% of the 3D group vs 60% in the 2D fluoroscopy group. At 2 years, there was no difference in number of revision surgery, complications, FAOS, AOFAS score, SF-36 score, or posttraumatic osteoarthritis., Conclusion: The use of intraoperative 3D fluoroscopy in the treatment of intra-articular calcaneal fractures prolongs the operative procedures without improving the quality of reduction and fixation. There was no benefit of intraoperative 3D fluoroscopy with regard to postoperative complications, quality of life, functional outcome, or posttraumatic osteoarthritis. Level of Evidence: Level I, prospective randomized controlled study.

Aims: The aim of this study was to investigate whether intraoperative 3D fluoroscopic imaging outperforms dorsal tangential views in the detection of dorsal cortex screw penetration after volar plating of an intra-articular distal radial fracture, as identified on postoperative CT imaging., Methods: A total of 165 prospectively enrolled patients who underwent volar plating for an intra-articular distal radial fracture were retrospectively evaluated to study three intraoperative imaging protocols: 1) standard 2D fluoroscopic imaging with anteroposterior (AP) and elevated lateral images (n = 55); 2) 2D fluoroscopic imaging with AP, lateral, and dorsal tangential views images (n = 50); and 3) 3D fluoroscopy (n = 60). Multiplanar reconstructions of postoperative CT scans served as the reference standard., Results: In order to detect dorsal screw penetration, the sensitivity of dorsal tangential views was 39% with a negative predictive value (NPV) of 91% and an accuracy of 91%; compared with a sensitivity of 25% for 3D fluoroscopy with a NPV of 93% and an accuracy of 93%. On the postoperative CT scans, we found penetrating screws in: 1) 40% of patients in the 2D fluoroscopy group; 2) in 32% of those in the 2D fluoroscopy group with AP, lateral, and dorsal tangential views; and 3) in 25% of patients in the 3D fluoroscopy group. In all three groups, the second compartment was prone to penetration, while the postoperative incidence decreased when more advanced imaging was used. There were no penetrating screws in the third compartment (extensor pollicis longus groove) in the 3D fluoroscopy groups, and one in the dorsal tangential views group., Conclusion: Advanced intraoperative imaging helps to identify screws which have penetrated the dorsal compartments of the wrist. However, based on diagnostic performance characteristics, one cannot conclude that 3D fluoroscopy outperforms dorsal tangential views when used for this purpose. Dorsal tangential views are sufficiently accurate to detect dorsal screw penetration, and arguably more efficacious than 3D fluoroscopy. Cite this article: Bone Joint J 2020;102-B(7):874-880.

Purpose: To allow physicians to be more selective in their request for a radiograph of the wrist and to potentially reduce costs, the Amsterdam Wrist Rules (AWR) have been developed, externally validated, and recently also implemented. The aim of this study was to conduct an incremental cost analysis and budget impact analysis of the implementation of the AWR at the emergency department (ED) in the Netherlands., Methods: A cost-minimisation analysis to determine the expected cost savings for implementation of the Amsterdam Wrist Rules. The incremental difference in costs before and after implementation of the AWR was based on the reduction in costs for radiographs, the cost savings due to reduction of ED consultation times and the costs of a re-evaluation appointment by a physician., Results: In the Netherlands, implementation of the AWR could potentially result in 6% cost savings per patient with a wrist injury. In addition, implementation of the AWR resulted in €203,510 cost savings annually nationwide. In the sensitivity analysis, an increase in physician compliance to 100% substantially increased the potential total amount of annual cost savings to €610,248, which is 6% of total costs before implementation. Variation in time spent at the ED, a decrease and increase in costs and patients presenting annually at the ED did not change the cost savings substantially., Conclusion: Implementation of the AWR has been shown to reduce direct and indirect costs and can, therefore, result in considerable savings of healthcare consumption and expenditure.

Background: Field triage of trauma patients is crucial to get the right patient to the right hospital within a particular time frame. Minimization of undertriage, overtriage, and interhospital transfer rates could substantially reduce mortality rates, life-long disabilities, and costs. Identification of patients in need of specialized trauma care is predominantly based on the judgment of Emergency Medical Services professionals and a pre-hospital triage protocol. The Trauma Triage App is a smartphone application that includes a prediction model to aid Emergency Medical Services professionals in the identification of patients in need of specialized trauma care. The aim of this trial is to assess the impact of this new digital approach to field triage on the primary endpoint undertriage., Methods: The Trauma triage using Supervised Learning Algorithms (TESLA) trial is a stepped-wedge cluster-randomized controlled trial with eight clusters defined as Emergency Medical Services regions. These clusters are an integral part of five inclusive trauma regions. Injured patients, evaluated on-scene by an Emergency Medical Services professional, suspected of moderate to severe injuries, will be assessed for eligibility. This unidirectional crossover trial will start with a baseline period in which the default pre-hospital triage protocol is used, after which all clusters gradually implement the Trauma Triage App as an add-on to the existing triage protocol. The primary endpoint is undertriage on patient and cluster level and is defined as the transportation of a severely injured patient (Injury Severity Score ≥ 16) to a lower-level trauma center. Secondary endpoints include overtriage, hospital resource use, and a cost-utility analysis., Discussion: The TESLA trial will assess the impact of the Trauma Triage App in clinical practice. This novel approach to field triage will give new and previously undiscovered insights into several isolated components of the diagnostic strategy to get the right trauma patient to the right hospital. The stepped-wedge design allows for within and between cluster comparisons., Trial Registration: Netherlands Trial Register, NTR7243. Registered 30 May 2018, https://www.trialregister.nl/trial/7038., Competing Interests: Competing interestsThe authors declare that they have no competing interests., (© The Author(s) 2020.)