Improving the management of open tibia fractures, Malawi.

Objective: To assess the impact of an open fracture intervention bundle on clinical management and patient outcomes of adults in Malawi with open tibia fractures. Methods: We conducted a before-and-after implementation study in Malawi in 2021 and 2022 to assess the impact of an open fracture intervention bundle, including a national education course for clinical officers and management guidelines for open fractures. We recruited 287 patients with open tibia fractures. The primary outcome was a before-and-after comparison of the self-reported short musculoskeletal function assessment score, a measure of patient function. Secondary outcomes included clinical management; and clinician knowledge and implementation evaluation outcomes of 57 health-care providers attending the course. We also constructed multilevel regression models to investigate associations between clinical knowledge, patient function, and implementation evaluation before and after the intervention. Findings: The median patient function score at 1 year was 6.8 (interquartile range, IQR: 1.5 to 14.5) before intervention and 8.4 (IQR: 3.8 to 23.2) after intervention. Compared with baseline scores, we found clinicians' open fracture knowledge scores improved 1 year after the intervention was implemented (mean posterior difference: 1.6, 95% highest density interval: 0.9 to 2.4). However, we found no difference in most aspects of clinicians' open fracture management practice. Conclusion: Despite possible improvement in clinician knowledge and positive evaluation of the intervention implementation, our study showed that there was no overall improvement in clinical management, and weak evidence of worsening patient function 1 year after injury, after implementation of the open fracture intervention bundle.

Stereotyped B-cell receptors in one-third of chronic lymphocytic leukemia: a molecular classification with implications for targeted therapies.

Mounting evidence indicates that grouping of chronic lymphocytic leukemia (CLL) into distinct subsets with stereotyped BCRs is functionally and prognostically relevant. However, several issues need revisiting, including the criteria for identification of BCR stereotypy and its actual frequency as well as the identification of "CLL-biased" features in BCR Ig stereotypes. To this end, we examined 7596 Ig VH (IGHV-IGHD-IGHJ) sequences from 7424 CLL patients, 3 times the size of the largest published series, with an updated version of our purpose-built clustering algorithm. We document that CLL may be subdivided into 2 distinct categories: one with stereotyped and the other with nonstereotyped BCRs, at an approximate ratio of 1:2, and provide evidence suggesting a different ontogeny for these 2 categories. We also show that subset-defining sequence patterns in CLL differ from those underlying BCR stereotypy in other B-cell malignancies. Notably, 19 major subsets contained from 20 to 213 sequences each, collectively accounting for 943 sequences or one-eighth of the cohort. Hence, this compartmentalized examination of VH sequences may pave the way toward a molecular classification of CLL with implications for targeted therapeutic interventions, applicable to a significant number of patients assigned to the same subset.

Pancreatic glucagonoma metastasising to the right ovary five years after initial surgery: a case report.

CONTEXT: Glucagonomas of the pancreas are neuroendocrine tumours (NETs) that arise from well-differentiated neuroendocrine cells within the pancreatic islets. They are considered to be aggressive NETs and often have metastases at initial presentation. In contrast localised glucagonoma without metastatic spread may have prolonged disease free survival with radical resectional surgery. CASE REPORT: The authors present a case of a glucagonoma that initially presented with classical necrolytic migratory erythema and a large solitary mass in the body and tail of the pancreas that was surgically resected. Five years after surgery the patient presented with increased serum glucagon levels and a mass in the right ovary. Pathology of the resected ovary after oophorectomy identified this as an isolated metastatic glucagonoma. CONCLUSION: Glucagonoma is a rare pancreatic NET that has significant malignant potential. This is the first case of a pancreatic glucagonoma metastasising to the ovary 5 years after radical distal pancreatosplenectomy.

Not Your Mother's Melanoma: Causes and Effects of Early Melanoma Diagnosis.

The year 2022 will herald approximately 100,000 new cases of cutaneous melanoma (CM), and over 7000 deaths from CM. Over the past 40 years, CM incidence has increased nearly six-fold; however, annual mortality has remained relatively constant. These trends encapsulate the phenomenon of overdiagnosis. Increased recognition of indolent lesions that appear histologically malignant may be leading to a melanoma epidemic. Enhanced melanoma awareness, screening efforts, physician uncertainty, medical-legal pressures, and diagnostic scrutiny using tools like immunohistochemical staining, mole mapping, dermoscopy, confocal microscopy, and molecular diagnostics contribute to increased CM diagnosis. As a result, current melanoma staging and treatment guidelines are being challenged. Existing standards fail to accurately identify histologically benign lesions that are lethal or, conversely, histologically malignant lesions that are innocuous. Healthcare systems and, more importantly, patients suffer from this diagnostic ambiguity that leads to the over-treatment of innocuous melanomas and under-treatment of aggressive melanomas. As dermatology continues to experience a shift towards earlier diagnosis of melanoma, management strategies must adapt. Herein, we review factors that may contribute to the increased incidence of melanoma, emphasize deficiencies in current staging systems, and provide insights into the future of melanoma management via precision medicine.

Experience with the Fassier-Duval telescopic rod: first 24 consecutive cases with a minimum of 1-year follow-up.

BACKGROUND: The new Fassier-Duval Telescopic IM System (FD-rod) has the advantage of a single entry point over the traditional telescopic rods such as the Bailey-Dubow or Sheffield rods. Although encouraging early results were presented by the originators of the technique at international meetings, there is no formal publication in the literature as yet. METHODS: We performed a chart and x-ray review of the first 24 consecutive FD-rod insertions in 15 patients (age, 1.5 to 12.5 y) with a minimum of 1-year follow up (1 to 2.4 y) after implantation of femoral and/or tibial FD-rods. Diagnoses included with osteogenesis imperfecta (OI) (15 cases, 9 patients), and other conditions such as congenital tibial pseudarthrosis (CPT) in neurofibromatosis type 1 (NF1) (2 cases), and epidermal naevus syndrome (1 case). In patients with hypophosphataemic rickets (6 cases, 2 patients) the FD-rods were combined with an Ilizarov frame. RESULTS: We found the OI patient group associated with a 13% reoperation rate (2 of 15 cases) for proximal rod migration and a 40% complication rate (6 of 15 cases): rod migration and limited telescoping (5) and intraoperative joint intrusion (1). There were no infections. All the NF1 CPT (2) and epidermal naevus syndrome (1) cases required several reoperations for nonunion, loss of fixation, shortening (negative telescoping), migration, and/or joint intrusion-mainly due to the severe underlying pathology with insufficient longitudinal or torsional stability and diminished healing capacity. In hypophosphataemic rickets (combined with Ilizarov frame fixation) we found a 50% complication rate (3 of 6 cases) and a 17% reoperation rate (1 of 6): 2 FD-rods did not telescope and 1 case of peroneal neuropraxia required neurolysis. CONCLUSIONS: In our experience the technique of using FD rods is demanding and associated with some intraoperative and postoperative pitfalls. We are happy to continue its use in OI patients when there is longitudinal stability and sufficient bone healing. However, in circumstances of insufficient stability and bone healing potential, further stabilization that can be achieved with an Ilizarov frame may be beneficial.

The CN-12: A Brief, Multidimensional Connection With Nature Instrument.

In recent decades, there has been increasing interest in (re)connecting people with nature to foster sustainability outcomes. There is a growing body of evidence suggesting a relationship between connection with nature and pro-environmental behaviors. Connection with nature has often been conceptualized as a unidimensional construct, and although recent evidence suggests that it is multidimensional, there is ongoing debate regarding the dimensions that make up connection with nature. Existing multidimensional connection with nature instruments capture similar dimensions, yet they are lengthy and may not have practical application in real-world contexts. This research sought to clarify the dimensions of connection with nature and to develop and validate an abbreviated yet multidimensional connection with nature instrument-the CN-12. Analyses of two large datasets revealed three dimensions of connection with nature-identity, experience, and philosophy. Results suggested that the CN-12 and its three dimensions are positively correlated with: (1) environmental and altruistic values; (2) time spent in nature; and (3) a range of pro-environmental behaviors. Results also suggested that the CN-12 and its three dimensions are stable over time and are positively correlated with two existing multidimensional connection with nature instruments, the Nature Relatedness (NR) Scale and Environmental Identity (EID) Scale. The utility of the CN-12 for exploring human connections with nature and the role of fostering connection with nature to increase engagement in pro-environmental behaviors are discussed.

Mesenchymal stem cells as a gene therapy carrier for treatment of fibrosarcoma.

BACKGROUND AIMS: Cell-based gene therapy is an alternative to viral and non-viral gene therapy. Emerging evidence suggests that mesenchymal stem cells (MSC) are able to migrate to sites of tissue injury and have immunosuppressive properties that may be useful in targeted gene therapy for sustained specific tissue engraftment. METHODS: In this study, we injected intravenously (i.v.) 1x10(6) MSC, isolated from green fluorescent protein (GFP) transgenic rats, into Rif-1 fibrosarcoma-bearing C3H/HeN mice. The MSC had been infected using a lentiviral vector to express stably the luciferase reporter gene (MSC-GFP-luci). An in vivo imaging system (IVIS 200) and Western blotting techniques were used to detect the distribution of MSC-GFP-luci in tumor-bearing animals. RESULTS: We observed that xenogenic MSC selectively migrated to the tumor site, proliferated and expressed the exogenous gene in subcutaneous fibrosarcoma transplants. No MSC distribution was detected in other organs, such as the liver, spleen, colon and kidney. We further showed that the FGF2/FGFR pathways may play a role in the directional movement of MSC to the Rif-1 fibrosarcoma. We performed in vitro co-culture and in vivo tumor growth analysis, showing that MSC did not affect the proliferation of Rif-1 cells and fibrosarcoma growth compared with an untreated control group. Finally, we demonstrated that the xenogenic MSC stably expressing inducible nitric oxide synthase (iNOS) protein transferred by a lentivirus-based system had a significant inhibitory effect on the growth of Rif-1 tumors compared with MSC alone and the non-treatment control group. CONCLUSIONS: iNOS delivered by genetically modified iNOS-MSC showed a significant anti-tumor effect both in vitro and in vivo. MSC may be used as a target gene delivery vehicle for the treatment of fibrosarcoma and other tumors.

Protocol for a randomised control trial of bisphosphonate (zoledronic acid) treatment in childhood femoral head avascular necrosis due to Perthes disease.

INTRODUCTION: Perthes disease (PD) is an idiopathic disorder presenting with avascular necrosis to the femoral head, which frequently results in flattening. Long-term function is directly related to the subsequent femoral head sphericity. Current treatment includes mechanical modalities and surgical procedures, which are therapeutic but are not uniformly able to prevent collapse. The use of the nitrogen-containing bisphosphonate zoledronic acid (ZA) to inhibit osteoclastic bone resorption is aimed at preserving femoral head strength, reducing collapse and thus maintaining shape. The proposed multicentre, prospective, randomised controlled trial intends to evaluate the efficacy of ZA treatment in PD. METHODS AND ANALYSIS: An open-label randomised control trial recruiting 100 children (50 each treatment arm) 5 to 16 years old with unilateral PD. Subjects are randomly assigned to either (a) ZA and standard care or (b) Standard care. The primary outcome measure is deformity index (DI), a radiographic parameter of femoral head roundness assessed at 24 months, following 12 months of ZA treatment (3-monthly doses of ZA 0.025 mg/kg at baseline, 3, 6, 9 and 12 months) plus 12 months observation (group A) or 24 months of observation (group B). Secondary outcome measures are femoral head subluxation, Faces Pain scale, Harris hip score and quality of life. Assessments are made at baseline, 3 monthly during the first year of follow-up and then 6 monthly, until the 24th month. ETHICS AND DISSEMINATION: The study commenced following the written approval from the Human Research Ethics Committee. Safety considerations regarding the effects of ZA are monitored which include the subject's symptomatology, mineral status, bone mass and turnover activity, and metaphyseal modelling. Data handling plan requires that all documents, clinical information, biological samples and investigation results will be held in strict confidence by study investigators to preserve its safety and confidentiality. TRIAL REGISTRATION NUMBER: Australian and New Zealand Clinical Trials ACTRN12610000407099, pre-results.

Who does not get cognitive-behavioral therapy for schizophrenia when therapy is readily available?

OBJECTIVE: The evidence base for using cognitive-behavioral therapy in schizophrenia is well established; it is recommended in guidelines by the Schizophrenia Patient Outcomes Research Team. METHODS: Data were examined regarding referral patterns for patients with schizophrenia who were seen by one of four psychiatrists at the mental health center providing services to West Southampton (England). RESULTS: Of the 142 patients identified, 69 had and 73 had not been referred for cognitive-behavioral therapy. Patients tended not to be referred if they were considered to be doing well and not in need of therapy or were unlikely to engage. CONCLUSIONS: In a location where cognitive-behavioral therapy for schizophrenia was readily available, half of all patients were considered appropriate for referral. Improved engagement skills and more assertive outreach by therapists and consideration by referrers of the benefits of relapse prevention might bring the benefits of cognitive-behavioral therapy to a still broader group.

Impact of genetic and non-genetic factors in type 1 diabetes.

Type 1 insulin-dependent diabetes is due to destruction of the insulin secreting cells of the islets of Langerhans. The disease is caused by non-genetic, probably environmental, factors operating in a genetically susceptible host to initiate a destructive immune process. These unknown environmental factors may operate over a limited period either in early or later and to a variable degree, playing a particularly substantial role in adults. The environment then induces an immune process associated with destruction of the islet beta cell that can be detected in early life and persists up to disease onset. Apart from an association with the insulin gene there is no evidence that genes associated with type 1 diabetes, including HLA and CTLA4 influence the targeting of the immune response to the insulin-secreting cells. The critical period of immune activation is probably short and the process leading to diabetes probably has a long prodrome but of variable duration that determines the age at presentation with clinical disease. The amplification both of this immune response and the destructive process is in part genetically determined, involving HLA genes. The clinical spectrum of the disease process associated with type 1 diabetes is wide, encompassing insulin-dependence, non-insulin dependence and even transient impaired glucose tolerance. Type 1 diabetes presenting in adults, in contrast to children, is predominantly determined by non-genetic factors with a reduced role for protective and susceptibility HLA alleles. Thus, the evidence is that genes involved in genetic susceptibility to type 1 diabetes operate predominantly in children not adults and in both amplify the immune response and the rate of disease progression.

Factors associated with bovine neonatal pancytopenia (BNP) in calves: a case-control study.

Bovine neonatal pancytopenia (BNP; previously known as idiopathic haemorrhagic diathesis and commonly known as bleeding calf syndrome) is a novel haemorrhagic disease of young calves which has emerged in a number of European countries during recent years. Data were retrospectively collected during June to November 2010 for 56 case calves diagnosed with BNP between 17 March and 7 June of the same year. These were compared with 58 control calves randomly recruited from herds with no history of BNP. Multivariable logistic regression analysis showed that increased odds of a calf being a BNP case were associated with its dam having received PregSure® BVD (Pfizer Animal Health) vaccination prior to the birth of the calf (odds ratio (OR) 40.78, p<0.001) and its herd of origin being located in Scotland (OR 9.71, p = 0.006). Decreased odds of a calf being a BNP case were associated with the calf having been kept outside (OR 0.11, p = 0.006). The longer that a cattle herd had been established on the farm was also associated with decreased odds of a calf in that herd being a BNP case (OR 0.97, p = 0.011).

Nitric oxide produced in response to engagement of beta2 integrins on human neutrophils activates the monomeric GTPases Rap1 and Rap2 and promotes adhesion.

We found that engagement of beta2 integrins on human neutrophils increased the levels of GTP-bound Rap1 and Rap2. Also, the activation of Rap1 was blocked by PP1, SU6656, LY294002, GF109203X, or BAPTA-AM, which indicates that the downstream signaling events in Rap1 activation involve Src tyrosine kinases, phosphoinositide 3-kinase, protein kinase C, and release of calcium. Surprisingly, the beta2 integrin-induced activation of Rap2 was not regulated by any of the signaling pathways mentioned above. However, we identified nitric oxide as the signaling molecule involved in beta2 integrin-induced activation of Rap1 and Rap2. This was illustrated by the fact that engagement of beta2 integrins increased the production of nitrite, a stable end-product of nitric oxide. Furthermore, pretreatment of neutrophils with Nomega-monomethyl-L-arginine, or 1400W, which are inhibitors of inducible nitric-oxide synthase, blocked beta2 integrin-induced activation of Rap1 and Rap2. Similarly, Rp-8pCPT-cGMPS, an inhibitor of cGMP-dependent serine/threonine kinases, also blunted the beta2 integrin-induced activation of Rap GTPases. Also nitric oxide production and its downstream activation of cGMP-dependent serine/threonine kinases were essential for proper neutrophil adhesion by beta2 integrins. Thus, we made the novel findings that beta2 integrin engagement on human neutrophils triggers production of nitric oxide and its downstream signaling is essential for activation of Rap GTPases and neutrophil adhesion.

Terapia de cicatriz hipertrófica e quelóide em mucosa bucal: relato de caso clínico / Hypertophic cicatrix and keloid therapy in oral mucosa: caso report

O presente trabalho aborda as características clínicas e histopatológicas das cicatrizes hipertróficas e quelóides, além do tratamento proposto atualmente na literatura. É relatado ainda, um caso clínico de cicatriz hipertrófica em mucosa interna de lábio superior, onde se utilizou, intralesionalmente, o acetato de triamcinolona como terapia