Does Early Conversion to Below-elbow Casting for Pediatric Diaphyseal Both-bone Forearm Fractures Adversely Affect Patient-reported Outcomes and ROM?

BACKGROUND: For distal forearm fractures in children, it has been shown that a below-elbow cast is an adequate treatment that overcomes the discomfort of an above-elbow cast and unnecessary immobilization of the elbow. For reduced diaphyseal both-bone forearm fractures, our previous randomized controlled trial (RCT)-which compared an above-elbow cast with early conversion to a below-elbow cast-revealed no differences in the risk of redisplacement or functional outcomes at short-term follow-up. Although studies with a longer follow-up after diaphyseal both-bone forearm fractures in children are scarce, they are essential, as growth might affect the outcome. QUESTIONS/PURPOSES: In this secondary analysis of an earlier RCT, we asked: (1) Does early conversion from an above-elbow to a below-elbow cast in children with reduced, stable diaphyseal forearm fractures result in worse clinical and radiological outcome? (2) Does a malunion result in inferior clinical outcomes at 7.5 years of follow-up? METHODS: In this study, we evaluated children at a minimum of 5 years of follow-up who were included in a previous RCT. The median (range) duration of follow-up was 7.5 years (5.2 to 9.9). The patients for this RCT were included from the emergency departments of four different urban hospitals. Between January 2006 and August 2010, we treated 128 patients for reduced diaphyseal both-bone forearm fractures. All 128 patients were eligible; 24% (31) were excluded because they were lost before the minimum study follow-up or had incomplete datasets, leaving 76% (97) for secondary analysis. The loss in the follow-up group was comparable to the included population. Eligible patients were invited for secondary functional and radiographic assessment. The primary outcome was the difference in forearm rotation compared with the uninjured contralateral arm. Secondary outcomes were the ABILHAND-kids and QuickDASH questionnaire, loss of flexion and extension of the elbow and wrist compared with the contralateral forearm, JAMAR grip strength ratio, and radiological assessment of residual deformity. The study was not blinded regarding the children, parents, and clinicians. RESULTS: At 7.5-year follow-up, there were no differences in ABILHAND-kids questionnaire score (above-elbow cast: 41 ± 2.4 versus above/below-elbow cast: 41.7 ± 0.7, mean difference -0.7 [95% confidence interval (CI) -1.4 to 0.04]; p = 0.06), QuickDASH (above-elbow cast: 5.8 ± 9.6 versus 2.9 ± 6.0 for above-/below-elbow cast, mean difference 2.9 [95% CI -0.5 to 6.2]; p = 0.92), and grip strength (0.9 ± 0.2 for above-elbow cast versus 1 ± 0.2 for above/below-elbow cast, mean difference -0.04 [95% CI -1 to 0.03]; p = 0.24). Functional outcomes showed no difference (loss of forearm rotation: above-elbow cast 7.9 ± 17.7 versus 4.1 ± 6.9 for above-/below-elbow cast, mean difference 3.8 [95% CI -1.7 to 9.4]; p = 0.47; arc of motion: above-elbow cast 152° ± 21° versus 155° ± 11° for the above/below-elbow cast group, mean difference -2.5 [95% CI -9.3 to -4.4]; p = 0.17; loss of wrist flexion-extension: above-elbow cast group 1.0° ± 5.0° versus 0.6° ± 4.2° for above/below-elbow cast, mean difference 0.4° [95% CI -1.5° to 2.2°]; p = 0.69). The secondary follow-up showed improvement in forearm rotation in both groups compared with the rotation at 7 months. For radiographical analysis, the only difference was in AP ulna (above-elbow cast: 6° ± 3° versus above/below-elbow cast: 5° ± 2°, mean difference 1.8° [0.7° to 3°]; p = 0.003), although this is likely not clinically relevant. There were no differences in the other parameters. Thirteen patients with persistent malunion at 7-month follow-up showed no clinically relevant differences in functional outcomes at 7.5-year follow-up compared with children without malunion. The loss of forearm rotation was 5.5ׄ° ± 9.1° for the malunion group compared with 6.0° ± 13.9° in the no malunion group, with a mean difference of 0.4 (95% CI of -7.5 to 8.4; p = 0.92). CONCLUSION: In light of these results, we suggest that surgeons perform an early conversion to a below-elbow cast for reduced diaphyseal both-bone forearm fractures in children. This study shows that even in patients with secondary fracture displacement, remodeling occurred. And even in persistent malunion, these patients mostly showed good-to-excellent final results. Future studies, such as a meta-analysis or a large, prospective observational study, would help to establish the influence of skeletal age, sex, and the severity and direction of malunion angulation of both the radius and ulna on clinical result. Furthermore, a similar systematic review could prove beneficial in clarifying the acceptable angulation for pediatric lower extremity fractures. LEVEL OF EVIDENCE: Level I, therapeutic study.

Transplantation and Noninvasive Longitudinal In Vivo Imaging of Parathyroid Cells: A Proof-of-Concept Study.

The parathyroid cell is a vital regulator of extracellular calcium levels, operating through the secretion of parathyroid hormone (PTH). Despite its importance, the regulation of PTH secretion remains complex and not fully understood, representing a unique interplay between extracellular and intracellular calcium, and hormone secretion. One significant challenge in parathyroid research has been the difficulty in maintaining cells ex vivo for in-depth cellular investigations. To address this issue, we introduce a novel platform for parathyroid cell transplantation and noninvasive in vivo imaging using the anterior chamber of the eye as a transplantation site. We found that parathyroid adenoma tissue transplanted into the mouse eye engrafted onto the iris, became vascularized, and retained cellular composition. Transplanted animals exhibited elevated PTH levels, indicating a functional graft. With in vivo confocal microscopy, we were able to repetitively monitor parathyroid graft morphology and vascularization. In summary, there is a pressing need for new methods to study complex cellular processes in parathyroid cells. Our study provides a novel approach for noninvasive in vivo investigations that can be applied to understand parathyroid physiology and pathology under physiological and pathological conditions. This innovative strategy can deepen our knowledge on parathyroid function and disease.

Elements of organisation of integrated maternity care and their associations with outcomes: a scoping review protocol.

INTRODUCTION: Integrated care is seen as an enabling strategy in organising healthcare to improve quality, finances, personnel and sustainability. Developments in the organisation of maternity care follow this trend. The way care is organised should support the general aims and outcomes of healthcare systems. Organisation itself consists of a variety of smaller 'elements of organisation'. Various elements of organisation are implemented in different organisations and networks. We will examine which elements of integrated maternity care are associated with maternal and neonatal health outcomes, experiences of women and professionals, healthcare spending and care processes. METHODS AND ANALYSIS: We will conduct this review using the JBI methodology for scoping reviews and the reporting guideline PRISMA-ScR (Preferred Reporting Items for Systematic Reviews and Meta-Analysis extension for Scoping Reviews). We will undertake a systematic search in the databases PubMed, Scopus, Cochrane and PsycINFO. A machine learning tool, ASReview, will be used to select relevant papers. These papers will be analysed and classified thematically using the framework of the Rainbow Model of Integrated Care (RMIC). The Population Concept Context framework for scoping reviews will be used in which 'Population' is defined as elements of the organisation of integrated maternity care, 'Context' as high-income countries and 'Concepts' as outcomes stated in the objective of this review. We will include papers from 2012 onwards, in Dutch or English language, which describe both 'how the care is organised' (elements) and 'outcomes'. ETHICS AND DISSEMINATION: Since this is a scoping review of previously published summary data, ethical approval for this study is not needed. Findings will be published in a peer-reviewed international journal, discussed in a webinar and presented at (inter)national conferences and meetings of professional associations.The findings of this scoping review will give insight into the nature and effectiveness of elements of integrated care and will generate hypotheses for further research.

Improved forearm rotation even after early conversion to below-elbow cast for non-reduced diaphyseal both-bones forearm fractures in children: a secondary 7.5-year follow up of a randomized trial.

BACKGROUND AND PURPOSE: previous RCT compared short-term results of above-elbow cast (AEC) with early conversion to below-elbow cast (BEC) in children with non-reduced diaphyseal both-bone forearm fractures. After 7 months both groups had comparable function. Our primary aim was to investigate whether forearm rotation improves or worsens over time. Secondary aims were loss of flexion and extension of the elbow and wrist, patient-reported outcomes measures, grip strength ratio, and radiographic assessment. PATIENTS AND METHODS: We performed long-term follow-up (FU) of a previous RCT. All patients were invited again for the long-term FU measurements. Primary outcome was limitation of forearm rotation. Secondary outcomes were loss of flexion and extension of the elbow and wrist compared with the contralateral forearm, the ABILHAND-Kids questionnaire and the Disabilities of the Arm, Shoulder and Hand (DASH) questionnaire, grip strength ratio, and radiographic assessment. RESULTS: The mean FU was 7.5 (4.4-9.6) years. Of the initial 47 children, 38 (81%) participated. Rotation improved in both groups over time, with no significant difference in the final forearm rotation: 8° (SD 22) for the AEC group and 8° (SD 15) for the BEC group with a mean difference of 0° (95% confidence interval -13 to 12). Secondary outcomes showed no statistically significant differences. Finally, children < 9 years almost all have full recovery of function. CONCLUSION: Long-term follow-up showed that loss of forearm rotation after a non-reduced diaphyseal both-bone forearm fracture improved significantly compared with that at 7 months, independent of the initial treatment and children aged < 9 will have almost full recovery of function. This substantiates that the remaining growth behaves like a "friend" at long-term follow-up.

Validation of the Rainbow Model of Integrated Care Measurement Tool in Parkinson's Disease.

BACKGROUND: Integrated care is essential for improving the management and health outcomes for people with Parkinson's disease (PD); reliable and objective measures of care integration are few. OBJECTIVE: The aim of this study was to test the psychometric properties of the Rainbow Model of Integrated Care Measurement Tool (RMIC-MT, provider version) for healthcare professionals involved in PD care. METHODS: A cross-sectional survey was administered online to an international network representing 95 neurology centers across 41 countries and 588 healthcare providers. Exploratory factor analysis with principal axis extraction method was used to assess construct validity. Confirmatory factor analysis was used to evaluate model fit of the RMIC-MT provider version. Cronbach's alpha was used to assess the internal consistency reliability. RESULTS: Overall, 371 care providers (62% response rate) participated in this study. No item had psychometric sensitivity problems. Nine factors (professional coordination, cultural competence, triple aims outcome, system coordination, clinical coordination, technical competence, community-centeredness, person-centeredness, and organizational coordination) with 42 items were determined by exploratory factor analysis. Cronbach's alpha ranged from 0.76 (clinical coordination) to 0.94 (system coordination) and showed significant correlation among all items in the scale (>0.4), indicating good internal consistency reliability. The confirmatory factor analysis model passed most goodness-of-fit tests, thereby confirming the factor structure of nine categories with a total of 40 items. CONCLUSIONS: The results provide evidence for the construct validity and other psychometric properties of the provider version of the RMIC-MT to measure integrated care in PD. © 2023 The Authors. Movement Disorders published by Wiley Periodicals LLC on behalf of International Parkinson and Movement Disorder Society.

Optimisation of scan duration and image quality in oncological 89Zr immunoPET imaging using the Biograph Vision PET/CT.

PURPOSE: Monoclonal antibody (mAb)-based PET (immunoPET) imaging can characterise tumour lesions non-invasively. It may be a valuable tool to determine which patients may benefit from treatment with a specific monoclonal antibody (mAb) and evaluate treatment response. For 89Zr immunoPET imaging, higher sensitivity of state-of-the art PET/CT systems equipped with silicon photomultiplier (SiPM)-based detector elements may be beneficial as the low positron abundance of 89Zr causes a low signal-to-noise level. Moreover, the long physical half-life limits the amount of activity that can be administered to the patients leading to poor image quality even when using long scan durations. Here, we investigated the difference in semiquantitative performance between the PMT-based Biograph mCT, our clinical reference system, and the SiPM-based Biograph Vision PET/CT in 89Zr immunoPET imaging. Furthermore, the effects of scan duration reduction using the Vision on semiquantitative imaging parameters and its influence on image quality assessment were evaluated. METHODS: Data were acquired on day 4 post 37 MBq 89Zr-labelled mAb injection. Five patients underwent a double scan protocol on both systems. Ten patients were scanned only on the Vision. For PET image reconstruction, three protocols were used, i.e. one camera-dependent protocol and European Association of Nuclear Medicine Research Limited (EARL) standards 1 and 2 compliant protocols. Vision data were acquired in listmode and were reprocessed to obtain images at shorter scan durations. Semiquantitative PET image parameters were derived from tumour lesions and healthy tissues to assess differences between systems and scan durations. Differently reconstructed images obtained using the Vision were visually scored regarding image quality by two nuclear medicine physicians. RESULTS: When images were reconstructed using 100% acquisition time on both systems following EARL standard 1 compliant reconstruction protocols, results regarding semiquantification were comparable. For Vision data, reconstructed images that conform to EARL1 standards still resulted in comparable semiquantification at shorter scan durations (75% and 50%) regarding 100% acquisition time. CONCLUSION: Scan duration of 89Zr immunoPET imaging using the Vision can be decreased up to 50% compared with using the mCT while maintaining image quality using the EARL1 compliant reconstruction protocol.

Whole-body CD8+ T cell visualization before and during cancer immunotherapy: a phase 1/2 trial.

Immune checkpoint inhibitors (ICIs), by reinvigorating CD8+ T cell mediated immunity, have revolutionized cancer therapy. Yet, the systemic CD8+ T cell distribution, a potential biomarker of ICI response, remains poorly characterized. We assessed safety, imaging dose and timing, pharmacokinetics and immunogenicity of zirconium-89-labeled, CD8-specific, one-armed antibody positron emission tomography tracer 89ZED88082A in patients with solid tumors before and ~30 days after starting ICI therapy (NCT04029181). No tracer-related side effects occurred. Positron emission tomography imaging with 10 mg antibody revealed 89ZED88082A uptake in normal lymphoid tissues, and tumor lesions across the body varying within and between patients two days after tracer injection (n = 38, median patient maximum standard uptake value (SUVmax) 5.2, IQI 4.0-7.4). Higher SUVmax was associated with mismatch repair deficiency and longer overall survival. Uptake was higher in lesions with stromal/inflamed than desert immunophenotype. Tissue radioactivity was localized to areas with immunohistochemically confirmed CD8 expression. Re-imaging patients on treatment showed no change in average (geometric mean) tumor tracer uptake compared to baseline, but individual lesions showed diverse changes independent of tumor response. The imaging data suggest enormous heterogeneity in CD8+ T cell distribution and pharmacodynamics within and between patients. In conclusion, 89ZED88082A can characterize the complex dynamics of CD8+ T cells in the context of ICIs, and may inform immunotherapeutic treatments.

Monocyte response after colorectal surgery: A prospective cohort study.

Background: Tumor resection is the common approach in patients with colorectal malignancy. Profound insight into inflammatory changes that accompany the normal post-operative stress response will establish reference parameters useful for identification of putative complications. Alterations in circulating monocytes might be indicative as these cells are considered to be the most responsive leukocytes to trauma. Therefore, the aim of this study is to assess the monocyte subset kinetic and phenotypic changes in response to surgery. Methods: Fifty patients undergoing colorectal tumor resection were included in a multicenter prospective cohort study. Blood samples were collected early in the morning prior to surgery and the next days through postoperative day three for flowcytometric analysis. Leukocyte subtypes were identified and expression of activation stage-related markers by monocyte subsets was quantified. Results: Changes in leukocyte subset composition and monocyte subset phenotypes were most prominent at the first day postoperatively, after which these parameters typically returned to normal or near-normal preoperative values. The immunophenotypic alterations after surgery were most notable in classical and intermediate monocytes. These included up-regulation of activation markers CD64 and CD62L, but down-regulation of HLA-DR and CD54. Markers of de-activation, CD163 and CD206, were consistently increasingly expressed. Discussion/conclusion: The current study gives detailed insight into the peripheral blood leukocyte response after colorectal cancer surgery. This form of short-term stress induces a rapid and significant redistribution of immune cells. Immunophenotypic alterations in monocytes as a response to surgery suggest a mixed profile of cellular activation and de-activation.

Quantitative 3D OPT and LSFM datasets of pancreata from mice with streptozotocin-induced diabetes.

Mouse models for streptozotocin (STZ) induced diabetes probably represent the most widely used systems for preclinical diabetes research, owing to the compound's toxic effect on pancreatic ß-cells. However, a comprehensive view of pancreatic ß-cell mass distribution subject to STZ administration is lacking. Previous assessments have largely relied on the extrapolation of stereological sections, which provide limited 3D-spatial and quantitative information. This data descriptor presents multiple ex vivo tomographic optical image datasets of the full ß-cell mass distribution in mice subject to single high and multiple low doses of STZ administration, and in glycaemia recovered mice. The data further include information about structural features, such as individual islet ß-cell volumes, spatial coordinates, and shape as well as signal intensities for both insulin and GLUT2. Together, they provide the most comprehensive anatomical record of the effects of STZ administration on the islet of Langerhans in mice. As such, this data descriptor may serve as reference material to facilitate the planning, use and (re)interpretation of this widely used disease model.

Molecular imaging to support cancer immunotherapy.

The advent of immune checkpoint inhibitors has reinvigorated the field of immuno-oncology. These monoclonal antibody-based therapies allow the immune system to recognize and eliminate malignant cells. This has resulted in improved survival of patients across several tumor types. However, not all patients respond to immunotherapy therefore predictive biomarkers are important. There are only a few Food and Drug Administration-approved biomarkers to select patients for immunotherapy. These biomarkers do not consider the heterogeneity of tumor characteristics across lesions within a patient. New molecular imaging tracers allow for whole-body visualization with positron emission tomography (PET) of tumor and immune cell characteristics, and drug distribution, which might guide treatment decision making. Here, we summarize recent developments in molecular imaging of immune checkpoint molecules, such as PD-L1, PD-1, CTLA-4, and LAG-3. We discuss several molecular imaging approaches of immune cell subsets and briefly summarize the role of FDG-PET for evaluating cancer immunotherapy. The main focus is on developments in clinical molecular imaging studies, next to preclinical studies of interest given their potential translation to the clinic.

Quantitative parameters of bacterial RNA polymerase open-complex formation, stabilization and disruption on a consensus promoter.

Transcription initiation is the first step in gene expression, and is therefore strongly regulated in all domains of life. The RNA polymerase (RNAP) first associates with the initiation factor $\sigma$ to form a holoenzyme, which binds, bends and opens the promoter in a succession of reversible states. These states are critical for transcription regulation, but remain poorly understood. Here, we addressed the mechanism of open complex formation by monitoring its assembly/disassembly kinetics on individual consensus lacUV5 promoters using high-throughput single-molecule magnetic tweezers. We probed the key protein-DNA interactions governing the open-complex formation and dissociation pathway by modulating the dynamics at different concentrations of monovalent salts and varying temperatures. Consistent with ensemble studies, we observed that RNAP-promoter open (RPO) complex is a stable, slowly reversible state that is preceded by a kinetically significant open intermediate (RPI), from which the holoenzyme dissociates. A strong anion concentration and type dependence indicates that the RPO stabilization may involve sequence-independent interactions between the DNA and the holoenzyme, driven by a non-Coulombic effect consistent with the non-template DNA strand interacting with $\sigma$ and the RNAP $\beta$ subunit. The temperature dependence provides the energy scale of open-complex formation and further supports the existence of additional intermediates.

89Zr-DFO-Durvalumab PET/CT Before Durvalumab Treatment in Patients with Recurrent or Metastatic Head and Neck Cancer.

In this PD-L1 ImagiNg to prediCt durvalumab treatment response in SCCHN (PINCH) study, we performed 89Zr-DFO-durvalumab (anti-PD-L1 [programmed death ligand 1]) PET/CT in patients with recurrent or metastatic (R/M) squamous cell carcinoma of the head and neck (SCCHN) before monotherapy durvalumab treatment. The primary aims were to assess safety and feasibility of 89Zr-DFO-durvalumab PET imaging and predict disease control rate during durvalumab treatment. Secondary aims were to correlate 89Zr-DFO-durvalumab uptake to tumor PD-L1 expression, 18F-FDG uptake, and treatment response of individual lesions. Methods: In this prospective multicenter phase I-II study (NCT03829007), patients with incurable R/M SCCHN underwent baseline 18F-FDG PET and CT or MRI. Subsequently, PD-L1 PET imaging was performed 5 d after administration of 37 MBq of 89Zr-DFO-durvalumab. To optimize imaging conditions, dose finding was performed in the first 14 patients. For all patients (n = 33), durvalumab treatment (1,500 mg/4 wk, intravenously) was started within 1 wk after PD-L1 PET imaging and continued until disease progression or unacceptable toxicity (maximum, 24 mo). CT evaluation was assessed according to RECIST 1.1 every 8 wk. PD-L1 expression was determined by combined positive score on (archival) tumor tissue. 89Zr-DFO-durvalumab uptake was measured in 18F-FDG-positive lesions, primary and secondary lymphoid organs, and blood pool. Results: In total, 33 patients with locoregional recurrent (n = 12) or metastatic SCCHN (n = 21) were enrolled. 89Zr-DFO-durvalumab injection was safe. A dose of 10 mg of durvalumab resulted in highest tumor-to-blood ratios. After a median follow-up of 12.6 mo, overall response rate was 26%. The disease control rate at 16 wk was 48%, with a mean duration of 7.8 mo (range, 1.7-21.1). On a patient level, 89Zr-DFO-durvalumab SUVpeak or tumor-to-blood ratio could not predict treatment response (hazard ratio, 1.5 [95% CI, 0.5-3.9; P = 0.45] and 1.3 [95% CI, 0.5-3.3; P = 0.60], respectively). Also, on a lesion level, 89Zr-DFO-durvalumab SUVpeak showed no substantial correlation to treatment response (Spearman ρ, 0.45; P = 0.051). Lesional 89Zr-DFO-durvalumab uptake did not correlate to PD-L1 combined positive score but did correlate to 18F-FDG SUVpeak (Spearman ρ, 0.391; P = 0.005). Conclusion: PINCH is the first, to our knowledge, PD-L1 PET/CT study in patients with R/M SCCHN and has shown the feasibility and safety of 89Zr-DFO-durvalumab PET/CT in a multicenter trial. 89Zr-DFO-durvalumab uptake did not correlate to durvalumab treatment response.

Laparoscopic peritoneal lavage versus sigmoidectomy for perforated diverticulitis with purulent peritonitis: three-year follow-up of the randomised LOLA trial.

BACKGROUND: This study aimed to compare laparoscopic lavage and sigmoidectomy as treatment for perforated diverticulitis with purulent peritonitis during a 36 month follow-up of the LOLA trial. METHODS: Within the LOLA arm of the international, multicentre LADIES trial, patients with perforated diverticulitis with purulent peritonitis were randomised between laparoscopic lavage and sigmoidectomy. Outcomes were collected up to 36 months. The primary outcome of the present study was cumulative morbidity and mortality. Secondary outcomes included reoperations (including stoma reversals), stoma rates, and sigmoidectomy rates in the lavage group. RESULTS: Long-term follow-up was recorded in 77 of the 88 originally included patients, 39 were randomised to sigmoidectomy (51%) and 38 to laparoscopic lavage (49%). After 36 months, overall cumulative morbidity (sigmoidectomy 28/39 (72%) versus lavage 32/38 (84%), p = 0·272) and mortality (sigmoidectomy 7/39 (18%) versus lavage 6/38 (16%), p = 1·000) did not differ. The number of patients who underwent a reoperation was significantly lower for lavage compared to sigmoidectomy (sigmoidectomy 27/39 (69%) versus lavage 17/38 (45%), p = 0·039). After 36 months, patients alive with stoma in situ was lower in the lavage group (proportion calculated from the Kaplan-Meier life table, sigmoidectomy 17% vs lavage 11%, log-rank p = 0·0268). Eventually, 17 of 38 (45%) patients allocated to lavage underwent sigmoidectomy. CONCLUSION: Long-term outcomes showed that laparoscopic lavage was associated with less patients who underwent reoperations and lower stoma rates in patients alive after 36 months compared to sigmoidectomy. No differences were found in terms of cumulative morbidity or mortality. Patient selection should be improved to reduce risk for short-term complications after which lavage could still be a valuable treatment option.

Oncostatin M promotes lipolysis in white adipocytes.

Oncostatin M (OSM) is a member of the glycoprotein 130 cytokine family that is involved in chronic inflammation and increased in adipose tissue under obesity and insulin resistance. OSM was shown to inhibit adipogenesis, suppress browning, and contribute to insulin resistance in cultured white adipocytes. In contrast, OSM may have a metabolically favourable role on adipocytes in mouse models of obesity and insulin resistance. However, a putative role of OSM in modulating lipolysis has not been investigated in detail to date. To address this, cultured white adipocytes of mouse or human origin were exposed to 10 or 100 ng/ml of OSM for various time periods. In murine 3T3-L1 cells, OSM stimulation directly activated hormone-sensitive lipase (HSL) and other players of the lipolytic machinery, and dose-dependently increased free fatty acid and glycerol release. In parallel, OSM attenuated insulin-mediated suppression of lipolysis and induced phosphorylation of serine-residues on the insulin receptor substrate-1 (IRS1) protein. Key experiments were verified in a second murine and a human adipocyte cell line. Inhibiton of extracellular signal-regulated kinase (ERK)-1/2 activation, abolished OSM-mediated HSL phosphorylation and lipolysis. In conclusion, OSM signalling directly promotes lipolysis in white adipocytes in an ERK1/2-dependent manner.

Hartmann's procedure versus sigmoidectomy with primary anastomosis for perforated diverticulitis with purulent or fecal peritonitis: Three-year follow-up of a randomised controlled trial.

BACKGROUND: The aim of the present study is to present the three years follow-up a randomised controlled trial that compared Hartmann's Procedure (HP) with sigmoidectomy with primary anastomosis (with or without defunctioning ileostomy) (PA) in a randomised design to determine the optimal treatment strategy for perforated diverticulitis with purulent or fecal peritonitis. METHODS: Data were prospectively gathered for the first 12 months after randomization and retrospectively collected up to 36 months. The primary long-term endpoint was stoma free rate 36 months after the index procedure. Secondary outcomes were patients with a stoma at 36 months, percentage of stoma reversals, related reinterventions, parastomal/incisional hernia rates, total in hospital days including all readmissions regardless their relation to the intervention, overall morbidity and mortality. RESULTS: Three years follow-up was completed in 119 of the originally 130 included patients, with 57 (48%) in the PA-group and 62 (52%) patients in the HP-group. 36 months stoma free rate was significantly better for patients undergoing PA compared with HP (PA 92% vs HP 81%, hazard ratio 2.326 [95% CI 1.538-3.517]; log-rank p < 0·0001). Stoma reversal rates did not significantly differ (PA 31/40(78%) versus HP 45/61(74%), p = 0.814). Overall cumulative morbidity (PA 21/57(36%) versus HP 30/62(48%), p = 0.266) and mortality (PA 6/57(11%) versus HP 7/62 (11%), p = 1.000) did not differ between groups. However, more parastomal hernias occurred in the HP-group (HP 10/62(16%) vs PA 1/57(2%), p = 0.009) and the mean total in hospital days after three years follow-up was significantly lower in the PA-group compared to the HP-group (PA 14 days (IQR 9.5-22.5) versus HP 17 days (IQR 12.5-27.5)), p = 0.025). CONCLUSION: Long-term results showed that in haemodynamically stable, immunocompetent patients primary anastomosis is superior to Hartmann's procedure as treatment for perforated diverticulitis with respect to long-term stoma free rate, overall hospitalization and parastomal hernias.

Do We Need to Stabilize All Reduced Metaphyseal Both-bone Forearm Fractures in Children with K-wires?

BACKGROUND: Short-term follow-up studies have shown that reduced metaphyseal both-bone forearm fractures in children should be treated with K-wires to prevent redisplacement and inferior functional results. Minimum 5-year follow-up studies are limited. Range of motion, patient-reported outcome measures, and radiographic parameters at minimum 5-year follow-up should be evaluated because they could change insights into how to treat pediatric metaphyseal forearm fractures. QUESTIONS/PURPOSES: (1) Does K-wire stabilization of reduced metaphyseal both-bone forearm fractures in children provide better forearm rotation at minimum 5-year follow-up? (2) Do malunions (untreated redisplaced fractures) of reduced metaphyseal both-bone forearm fractures in children induce worse functional results? (3) Which factors lead to limited forearm rotation at minimum 5-year follow-up? METHODS: We analyzed the extended minimum 5-year follow-up of a randomized controlled trial in which children with a reduced metaphyseal both-bone forearm fracture were randomized to either an above-elbow cast (casting group) or fixation with K-wires and an above-elbow cast (K-wire group). Between January 2006 and December 2010, 128 patients were included in the original randomized controlled trial: 67 in the casting group and 61 in the K-wire group. For the current study, based on an a priori calculation, it was determined that, with an anticipated mean limitation in prosupination (forearm rotation) of 7° ± 7° in the casting group and 3° ± 5° in the K-wire group, a power of 80% and a significance of 0.05, the two groups should consist of 50 patients each. Between January 2014 and May 2016, 82% (105 of 128) of patients were included, with a mean follow-up of 6.8 ± 1.4 years: 54 in the casting group and 51 in the K-wire group. At trauma, patients had a mean age of 9 ± 3 years and had mean angulations of the radius and ulna of 25° ± 14° and 23° ± 18°, respectively. The primary result was limitation in forearm rotation. Secondary outcome measures were radiologic assessment, patient-reported outcome measures (QuickDASH and ABILHAND-kids), handgrip strength, and VAS score for cosmetic appearance. Assessments were performed by the first author (unblinded). Multivariable logistic regression analysis was performed to analyze which factors led to a clinically relevant limitation in forearm rotation. RESULTS: There was a mean limitation in forearm rotation of 5° ± 11° in the casting group and 5° ± 8° in the K-wire group, with a mean difference of 0.3° (95% CI -3° to 4°; p = 0.86). Malunions occurred more often in the casting group than in the K-wire group: 19% (13 of 67) versus 7% (4 of 61) with an odds ratio of 0.22 for K-wiring (95% CI 0.06 to 0.80; p = 0.02). In patients in whom a malunion occurred (malunion group), there was a mean limitation in forearm rotation of 6° ± 16° versus 5° ± 9° in patients who did not have a malunion (acceptable alignment group), with a mean difference 0.8° (95% CI -5° to 7°; p = 0.87). Factors associated with a limited forearm rotation ≥ 20° were a malunion after above-elbow casting (OR 5.2 [95% CI 1.0 to 27]; p = 0.045) and a refracture (OR 7.1 [95% CI 1.4 to 37]; p = 0.02). CONCLUSION: At a minimum of 5 years after injury, in children with a reduced metaphyseal both-bone forearm fracture, there were no differences in forearm rotation, patient-reported outcome measures, or radiographic parameters between patients treated with only an above-elbow cast compared with those treated with additional K-wire fixation. Redisplacements occurred more often if treated by an above-elbow cast alone. If fracture redisplacement is not treated promptly, this leads to a malunion, which is a risk factor for a clinically relevant (≥ 20°) limitation in forearm rotation at minimum 5-year follow-up. Children with metaphyseal both-bone forearm fractures can be treated with closed reduction and casting without additional K-wire fixation. Nevertheless, a clinician should inform parents and patient about the high risk of fracture redisplacement (and therefore malunion), with risk for limited forearm rotation if left untreated. Weekly radiographic monitoring is essential. If redisplacement occurs, remanipulation and fixation with K-wires should be considered based on gender, age, and direction of angulation. Future research is required to establish the influence of (skeletal) age, gender, and the direction of malunion angulation on clinical outcome. LEVEL OF EVIDENCE: Level I, therapeutic study.

Calcification of the Aorta-Iliac Trajectory as a Risk Factor for Anastomotic Leakage in Colorectal Surgery: Individual Patient Data Meta-Analysis and Systematic Review.

OBJECTIVE: The purpose of this review is to evaluate the relevance of vascular calcification as a potential risk factor for anastomotic leakage in colorectal surgery. METHOD: The Embase, Medline, PubMed, and Cochrane databases and Google Scholar were systematically searched. Studies that assessed calcification of the aorta-iliac trajectory in patients who underwent colorectal surgery were included. An independent patient data meta-analysis was performed as follows: based on the heterogeneity of the study population, a "random-effects model" or "fixed-effects model" was used to perform a multivariable logistic regression and calculate pooled Odds Ratios (OR) and 95% confidence intervals (CI). Heterogeneity was assessed using the Q-test and I2-test. RESULTS: From a total of 457 articles retrieved, eight fell within the scope of the review, with a total of 2010 patients. Anastomotic leakage was found at a mean rate of 11.1% (SD 4.9%). In these eight studies, four different calcification scoring methods were used, which made a single structured meta-analysis not feasible. Therefore, an independent patient data meta-analysis on the most frequently used calcification scoring method was performed, including three studies with a total of 396 patients. After multivariable analyses, no significant association was found between anastomotic leakage and the amount of calcification in the aorta-iliac trajectory. The remaining three scoring methods were evaluated. In four of the five studies, vascular calcification was associated with anastomotic leakage after colorectal surgery. CONCLUSION: In contrast to previous studies, an individual patient data meta-analysis found no association between calcification and anastomotic leakage in colorectal surgery after multivariable analysis that considered a single calcification measurement method. In addition, this study demonstrated several scoring methods for arterial calcification and the need for a standardized technique. Therefore, the authors would recommend prospective studies using a calcification scoring method that includes grade of stenosis due to its potential to preoperatively improve perfusion by endovascular treatment.

Oncostatin M suppresses browning of white adipocytes via gp130-STAT3 signaling.

OBJECTIVE: Obesity is associated with low-grade adipose tissue inflammation and locally elevated levels of several glycoprotein 130 (gp130) cytokines. The conversion of white into brown-like adipocytes (browning) may increase energy expenditure and revert the positive energy balance that underlies obesity. Although different gp130 cytokines and their downstream targets were shown to regulate expression of the key browning marker uncoupling protein 1 (Ucp1), it remains largely unknown how this contributes to the development and maintenance of obesity. Herein, we aim to study the role of gp130 cytokine signaling in white adipose tissue (WAT) browning in the obese state. METHODS: Protein and gene expression levels of UCP1 and other thermogenic markers were assessed in a subcutaneous adipocyte cell line, adipose tissue depots from control or adipocyte-specific gp130 knockout (gp130Δadipo) mice fed either chow or a high-fat diet (HFD), or subcutaneous WAT biopsies from a human cohort of lean and obese subjects. WAT browning was modeled in vitro by exposing mature adipocytes to isoproterenol after stimulation with gp130 cytokines. ERK and JAK-STAT signaling were blocked using the inhibitors U0126 and Tofacitinib, respectively. RESULTS: Inguinal WAT of HFD-fed gp130Δadipo mice exhibited significantly elevated levels of UCP1 and other browning markers such as Cidea and Pgc-1α. In vitro, treatment with the gp130 cytokine oncostatin M (OSM) lowered isoproterenol-induced UCP1 protein and gene expression levels in a dose-dependent manner. Mechanistically, OSM mediated the inhibition of Ucp1 via the JAK-STAT but not the ERK pathway. As with mouse data, OSM gene expression in human WAT positively correlated with BMI (r = 0.284, p = 0.021, n = 66) and negatively with UCP1 expression (r = -0.413, p < 0.001, n = 66). CONCLUSIONS: Our data support the notion that OSM negatively regulates thermogenesis in WAT and thus may be an attractive target for treating obesity.

Interleukin-2 PET imaging in patients with metastatic melanoma before and during immune checkpoint inhibitor therapy.

PURPOSE: Immune checkpoint inhibitors can induce a T cell-mediated anti-tumor immune response in patients with melanoma. Visualizing T cell activity using positron emission tomography (PET) might allow early insight into treatment efficacy. Activated tumor-infiltrating T cells express the high-affinity interleukin-2 receptor (IL-2R). Therefore, we performed a pilot study, using fluorine-18-labeled IL-2 ([18F]FB-IL2 PET), to evaluate whether a treatment-induced immune response can be detected. METHODS: Patients with metastatic melanoma received ~ 200 MBq [18F]FB-IL2 intravenously, followed by a PET/CT scan before and during immune checkpoint inhibitor therapy. [18F]FB-IL2 uptake was measured as standardized uptake value in healthy tissues (SUVmean) and tumor lesions (SUVmax). Response to therapy was assessed using RECIST v1.1. Archival tumor tissues were used for immunohistochemical analyses of T cell infiltration. RESULTS: Baseline [18F]FB-IL2 PET scans were performed in 13 patients. SUVmean at baseline was highest in the kidneys (14.2, IQR: 11.6-18.0) and liver (10.6, IQR: 8.6-13.4). In lymphoid tissues, uptake was highest in spleen (10.9, IQR: 8.8-12.4) and bone marrow (2.5, IQR: 2.1-3.0). SUVmax in tumor lesions (n = 41) at baseline was 1.9 (IQR: 1.7-2.3). In 11 patients, serial imaging was performed, three at week 6, seven at week 2, and one at week 4. Median [18F]FB-IL2 tumor uptake decreased from 1.8 (IQR: 1.7-2.1) at baseline to 1.7 (IQR: 1.4-2.1) during treatment (p = 0.043). Changes in [18F]FB-IL2 tumor uptake did not correlate with response. IL-2R expression in four archival tumor tissues was low and did not correlate with baseline [18F]FB-IL2 uptake. No [18F]FB-IL2-related side effects occurred. CONCLUSION: PET imaging of the IL-2R, using [18F]FB-IL2, is safe and feasible. In this small patient group, serial [18F]FB-IL2-PET imaging did not detect a treatment-related immune response. TRIAL REGISTRATION: Clinicaltrials.gov : NCT02922283; EudraCT: 2014-003387.20.

Cross-sectional study evaluating the association between integrated care and health-related quality of life (HRQOL) in Dutch primary care.

OBJECTIVES: The aim of this study was to evaluate the association between integrated care and health-related quality of life (HRQOL) in a primary care practice population. DESIGN: A cross-sectional survey study. SETTING: Primary care practice population. PARTICIPANTS: A sample (n=5562) of patients in two general practitioner practices in the Netherlands. PRIMARY OUTCOME MEASURES: The Rainbow Model of Integrated Care Measurement Tool patient version and EQ-5D was used to assess integrated service delivery and HRQOL. The association between integrated care and HRQOL groups was analysed using multivariate logistic regression. RESULTS: Overall, 933 respondents with a mean age of 62 participated (20% response rate) in this study. The multivariate analysis revealed that positive organisational coordination experiences were linked to better HRQOL (OR=1.87, 95% CI 1.18 to 2.95), and less anxiety and depression problems (OR=0.36, 95% CI 0.20 to 0.63). Unemployment was associated with a poor HRQOL (OR=0.15, 95% CI 0.08 to 0.28). Ageing was associated with more mobility (OR=1.06, 95% CI 1.04 to 1.09), self-care (OR=1.06, 95% CI 1.02 to 1.11), usual activity (OR=1.03, 95% CI 1.01 to 1.05) and pain problems (OR=1.02, 95% CI 1.01 to 1.04). Being married improved the overall HRQOL (OR=1.60, 95% CI 1.13 to 2.26) and decreased anxiety and depression (OR=0.47, 95% CI 0.31 to 0.72). Finally, females had a poor overall HRQOL (OR=1.67, 95% CI 0.48 to 0.93) and more pain and discomfort problems (OR=1.47, 95% CI 1.11 to 1.95). CONCLUSION: This study shows for the first time that organisational coordination activities are positively associated with HROQL of adult patients in a primary care context, adding to the evidence of an association between integrated care and HRQOL. Also, unemployment, ageing and being female are accumulating risk factors that should be considered when designing integrated primary care programmes. Further research is needed to explore how various integration types relate to HRQOL for people in local communities.