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Clodagh Keohane, Deepti H Radia, Claire N HarrisonDepartment of Haematology, Guy's and St Thomas' NHS Foundation Trust, London, UKAbstract: Myelofibrosis (MF) can present as a primary disorder or evolve from polycythemia vera (PV) or essential thrombocythemia (ET) to post-PV MF or post-ET MF, respectively. MF is characterized by bone marrow fibrosis, splenomegaly, leukoerythroblastosis, extramedullary hematopoiesis, and a collection of debilitating symptoms. Until recently, the therapeutic options for patients with MF consisted of allogeneic hematopoietic stem cell transplant (alloHSCT), the use of cytoreductive agents (ie, hydroxyurea), splenectomy and splenic irradiation for treatment of splenomegaly, and management of anemia with transfusions, erythropoiesis-stimulating agents (ESAs), androgens, and immunomodulatory agents. However, with increased understanding of the pathogenesis of MF resulting from dysregulated Janus kinase (JAK) signaling, new targeted JAK inhibitor therapies, such as ruxolitinib, are now available. The purpose of this article is to review the clinical features of MF, discuss the use and future of JAK inhibitors, reassess when and how to use conventional MF treatments in the context of JAK inhibitors, and provide a perspective on the future of MF treatment.Keywords: myelofibrosis, ruxolitinib, JAK inhibitor

A case is reported of Creutzfeldt-Jakob disease associated with amyloid infiltration of cerebral vessels. The duration of progressive dementia was only 4 months. Neuritic plaques were not a feature of the pathology. This report emphasises the association of spongiform encephalopathy with the presence of amyloid in the brain. [ABSTRACT FROM AUTHOR]

PURPOSE: Given the likely proliferation of targeted testing and treatment strategies for cancer, a better understanding of the utilization patterns of human epidermal growth factor receptor 2 (HER2) testing and trastuzumab and newer gene expression profiling (GEP) for risk stratification and chemotherapy decision making are important. STUDY DESIGN: Cross-sectional. METHODS: We performed a medical record review of women age 35 to 65 years diagnosed between 2006 and 2007 with invasive localized breast cancer, identified using claims from a large national health plan (N = 775). RESULTS: Almost all women received HER2 testing (96.9%), and 24.9% of women with an accepted indication received GEP. Unexplained socioeconomic differences in GEP use were apparent after adjusting for age and clinical characteristics; specifically, GEP use increased with income. For example, those in the lowest income category (< $40,000) were less likely than those with an income of $125,000 or more to receive GEP (odds ratio, 0.34; 95% CI, 0.16 to 0.73). A majority of women (57.7%) with HER2-positive disease received trastuzumab; among these women, differences in age and clinical characteristics were not apparent, although surprisingly, those in the lowest income category were more likely than those in the high-income category to receive trastuzumab (P = .02). Among women who did not have a positive HER2 test, 3.9% still received trastuzumab. Receipt of adjuvant chemotherapy increased as GEP score indicated greater risk of recurrence. CONCLUSION: Identifying and eliminating unnecessary variation in the use of these expensive tests and treatments should be part of quality improvement and efficiency programs.

A case of chondroblastoma of the temporal bone is reported, and the pathology of the lesion outlined. The rarity of these neoplasms in the skull makes accurate prognosis impossible. [ABSTRACT FROM AUTHOR]

Background: Neonatal encephalopathy (NE) continues to be a significant risk for death and disability. To address this risk, regional guidelines were developed with the support of a malpractice insurance patient safety organization. A NE registry was also established to include 14 centers representing around 50% of deliveries in the state of Massachusetts. The aim of this study was to identify areas of variation in practice that could benefit from quality improvement projects., Methods: This manuscript reports on the establishment of the registry and the primary findings to date., Results: From 2018 to 2020, 502 newborns with NE were evaluated for Therapeutic Hypothermia (TH), of which 246 (49%) received TH, representing a mean of 2.91 per 1000 live births. The study reports on prenatal characteristics, delivery room resuscitation, TH eligibility screening, and post-natal management of newborns with NE who did and did not receive TH., Conclusions: The registry has allowed for the identification of areas of variation in clinical practices, which have guided ongoing quality improvement projects. The authors advocate for the establishment of local and regional registries to standardize and improve NE patient care. They have made the registry data collection tools freely available for other centers to replicate this work., Impact: Malpractice insurance companies can take an active role in supporting clinicians in establishing clinical practice guidelines and regional registries. Establishing a collaborative regional neonatal encephalopathy (NE) registry is feasible. Data Collection tools for a NE registry have been made publicly available to be adopted and replicated by other groups. Establishing a regional NE registry allowed for the identification of gaps in knowledge, variations in practice, and the opportunity to advance care through quality improvement projects., (© 2023. The Author(s), under exclusive licence to the International Pediatric Research Foundation, Inc.)

A 72-year-old man was referred to our urology outpatient department with a left hemi-scrotal swelling increasing in size over a matter of weeks, initially suspicious for a left hydrocoele. Initial investigation with ultrasound (US) identified a heterogenous enlargement of the left testis and epididymis with a soft tissue mass extending through the inguinal canal. Subsequent CT detected this soft tissue mass to extend along the left gonadal vein to the level of the left renal vein. A biopsy of the retroperitoneal mass confirmed a diagnosis of diffuse large B-cell lymphoma. Immunohistochemical staining further categorised this lymphoma as double expressor but not double hit.Through multidisciplinary team involvement the patient was treated with combination steroids and chemotherapy. Given the scrotal involvement this was considered a sanctuary site for chemotherapy therefore the patient also received radiotherapy to the scrotum. He recovered well following his treatment. This case highlights how early specialist referral can identify rare variants of disease. Essential preoperative imaging with US prior to treating a presumed hydrocoele prevented inappropriate surgical excision. A multidisciplinary team approach improved the patient's outcome and is hoped to have improved his chances of recurrence-free survival., Competing Interests: Competing interests: None declared., (© BMJ Publishing Group Limited 2021. No commercial re-use. See rights and permissions. Published by BMJ.)

Background: Venous leg ulceration is a widespread, debilitating pathology with high recurrence rates. Conservative treatment using graduated compression dressings may be associated with unacceptable ulcer recurrence rates. Early superficial venous ablation encourages ulcer healing and reduces recurrence. However, many of this cohort display concomitant ilio-caval stenosis, which further contributes to lower limb venous hypertension and ulceration. An approach that combines early superficial venous ablation with early treatment of ilio-caval stenotic disease may significantly improve ulcer healing and recurrence rates. We question whether early iliac vein interrogation with intravascular ultrasound (IVUS), stenting of significant occlusive disease plus superficial venous ablation, in patients with active venous leg ulceration, will produce superior ulcer healing to standard therapy., Methods: This is a prospective, multi-centre, randomised controlled, feasibility trial recruiting patients with lower limb venous ulceration and saphenous venous incompetence. Patients will be randomised to undergo either truncal ablation and compression therapy or truncal ablation, simultaneous iliac interrogation with intravascular ultrasound and stenting of significant (> 50%) iliac vein lesions plus compression therapy. The primary feasibility outcome will be the rate of eligible patient participation while the primary clinical outcomes will be ulcer healing and procedural safety. Secondary outcomes include time to healing, quality of life and clinical scores, ulcer recurrence rates and rates of post-thrombotic syndrome. Follow-up will be over a 5-year period. This feasibility trial is designed to include 60 patients. Should it be practicable a total of 594 patients would be required to adequately power the trial to definitively address ulcer-healing rates., Discussion: This trial will be the first randomised trial to examine the role iliac interrogation and intervention in conjunction with standard operative therapy in the management of venous ulceration related to superficial truncal venous incompetence., Ethical Committee Reference: C.A. 2111 Galway Clinical Research Ethics Committee REGISTRATION: Clinical Trials.gov registration NCT03640689 , Registered on 21 August 2018.

Accurate pathological diagnosis is crucial for optimal management of patients with cancer. For the approximately 100 known tumour types of the central nervous system, standardization of the diagnostic process has been shown to be particularly challenging-with substantial inter-observer variability in the histopathological diagnosis of many tumour types. Here we present a comprehensive approach for the DNA methylation-based classification of central nervous system tumours across all entities and age groups, and demonstrate its application in a routine diagnostic setting. We show that the availability of this method may have a substantial impact on diagnostic precision compared to standard methods, resulting in a change of diagnosis in up to 12% of prospective cases. For broader accessibility, we have designed a free online classifier tool, the use of which does not require any additional onsite data processing. Our results provide a blueprint for the generation of machine-learning-based tumour classifiers across other cancer entities, with the potential to fundamentally transform tumour pathology.

Primitive neuroectodermal tumors of the central nervous system (CNS-PNETs) are highly aggressive, poorly differentiated embryonal tumors occurring predominantly in young children but also affecting adolescents and adults. Herein, we demonstrate that a significant proportion of institutionally diagnosed CNS-PNETs display molecular profiles indistinguishable from those of various other well-defined CNS tumor entities, facilitating diagnosis and appropriate therapy for patients with these tumors. From the remaining fraction of CNS-PNETs, we identify four new CNS tumor entities, each associated with a recurrent genetic alteration and distinct histopathological and clinical features. These new molecular entities, designated "CNS neuroblastoma with FOXR2 activation (CNS NB-FOXR2)," "CNS Ewing sarcoma family tumor with CIC alteration (CNS EFT-CIC)," "CNS high-grade neuroepithelial tumor with MN1 alteration (CNS HGNET-MN1)," and "CNS high-grade neuroepithelial tumor with BCOR alteration (CNS HGNET-BCOR)," will enable meaningful clinical trials and the development of therapeutic strategies for patients affected by poorly differentiated CNS tumors., (Copyright © 2016 Elsevier Inc. All rights reserved.)

Objective: The Leapfrog CPOE evaluation tool has been promoted as a means of monitoring computerized physician order entry (CPOE). We sought to determine the relationship between Leapfrog scores and the rates of preventable adverse drug events (ADE) and potential ADE., Materials and Methods: A cross-sectional study of 1000 adult admissions in five community hospitals from October 1, 2008 to September 30, 2010 was performed. Observed rates of preventable ADE and potential ADE were compared with scores reported by the Leapfrog CPOE evaluation tool. The primary outcome was the rate of preventable ADE and the secondary outcome was the composite rate of preventable ADE and potential ADE., Results: Leapfrog performance scores were highly related to the primary outcome. A 43% relative reduction in the rate of preventable ADE was predicted for every 5% increase in Leapfrog scores (rate ratio 0.57; 95% CI 0.37 to 0.88). In absolute terms, four fewer preventable ADE per 100 admissions were predicted for every 5% increase in overall Leapfrog scores (rate difference -4.2; 95% CI -7.4 to -1.1). A statistically significant relationship between Leapfrog scores and the secondary outcome, however, was not detected., Discussion: Our findings support the use of the Leapfrog tool as a means of evaluating and monitoring CPOE performance after implementation, as addressed by current certification standards., Conclusions: Scores from the Leapfrog CPOE evaluation tool closely relate to actual rates of preventable ADE. Leapfrog testing may alert providers to potential vulnerabilities and highlight areas for further improvement.

Background: It is uncertain if computerized physician order entry (CPOE) systems are effective at reducing adverse drug event (ADE) rates in community hospitals, where mainly vendor-developed applications are used., Objective: To evaluate the impact of vendor CPOE systems on the frequency of ADEs., Design and Patients: Prospective before-and-after study conducted from January 2005 to September 2010 at five Massachusetts community hospitals. Participants were adults admitted during the study period. A total of 2,000 charts were reviewed for orders, medication lists, laboratory reports, admission histories, notes, discharge summaries, and flow sheets., Main Measures: The primary outcome measure was the rate of preventable ADEs. Rates of potential ADEs and overall ADEs were secondary outcomes., Key Results: The rate of preventable ADEs decreased following implementation (10.6/100 vs. 7.0/100 admissions; p = 0.007) with a similar effect observed at each site. However, the associated decrease in preventable ADEs was balanced against an increase in potential ADEs (44.4/100 vs. 57.5/100 admissions; p < 0.001). We observed a reduction of 34.0% for preventable ADEs, but an increase of 29.5% in potential ADEs following implementation. The overall rate of ADEs increased (14.6/100 vs. 18.7/100 admissions; p = 0.03), which was driven by non-preventable events (4.0/100 vs. 11.7/100 admissions; p < 0.001)., Conclusions: Adoption of vendor CPOE systems was associated with a decrease in the preventable ADE rate by a third, although the rates of potential ADEs and overall ADEs increased. Our findings support the use of vendor CPOE systems as a means to reduce drug-related injury and harm. The potential ADE rate could be reduced by making refinements to the vendor applications and their associated decision support.

We describe a case of giant spinal ependymoma of cervicothoracic spine in a 30-year-old lady who presented with progressive spastic paraparesis and significant combined upper and lower motor neuron signs in her lower limbs over a 1-year period. She also had upper limb small muscle wasting with absent reflexes and diminished sensation. She was wheel chair bound with involvement of sphincters. Neuroimaging revealed a uniformly enhancing intramedullary lesion from C2-T3 level with associated syringomyelia. She underwent a complete excision of this World Health Organisation (WHO) II cellular ependymoma, resulting in significant clinical outcome and improvement in bladder and bowel function.

Objective: To evaluate the impact of a real-time computerized decision support tool in the emergency department that guides medication dosing for the elderly on physician ordering behavior and on adverse drug events (ADEs)., Design: A prospective controlled trial was conducted over 26 weeks. The status of the decision support tool alternated OFF (7/17/06-8/29/06), ON (8/29/06-10/10/06), OFF (10/10/06-11/28/06), and ON (11/28/06-1/16/07) in consecutive blocks during the study period. In patients ≥65 who were ordered certain benzodiazepines, opiates, non-steroidals, or sedative-hypnotics, the computer application either adjusted the dosing or suggested a different medication. Physicians could accept or reject recommendations., Measurements: The primary outcome compared medication ordering consistent with recommendations during ON versus OFF periods. Secondary outcomes included the admission rate, emergency department length of stay for discharged patients, 10-fold dosing orders, use of a second drug to reverse the original medication, and rate of ADEs using previously validated explicit chart review., Results: 2398 orders were placed for 1407 patients over 1548 visits. The majority (49/53; 92.5%) of recommendations for alternate medications were declined. More orders were consistent with dosing recommendations during ON (403/1283; 31.4%) than OFF (256/1115; 23%) periods (p≤0.0001). 673 (43%) visits were reviewed for ADEs. The rate of ADEs was lower during ON (8/237; 3.4%) compared with OFF (31/436; 7.1%) periods (p=0.02). The remaining secondary outcomes showed no difference., Limitations: Single institution study, retrospective chart review for ADEs., Conclusion: Though overall agreement with recommendations was low, real-time computerized decision support resulted in greater acceptance of medication recommendations. Fewer ADEs were observed when computerized decision support was active.

The authors describe an unusual case of metastatic thyroid follicular adenocarcinoma presenting with sciatica in a 79-year-old woman. The primary thyroid tumour was undiagnosed until this clinical presentation. The patient gave a short history of back pain and right-sided sciatica, which was progressive and nocturnal in nature. Neuroimaging revealed an enhancing intradural mass lesion, which was completely excised through a right L1-L3 hemilaminectomy. Histopathological examination of the excised tissue revealed a follicular thyroid carcinoma. Subsequent metastatic investigation revealed a heterogeneously attenuating mixed solid cystic mass in a retrosternal thyroid gland, with multiple solid pulmonary nodules suggestive of metastatic disease. She opted for palliative radiotherapy for the primary thyroid cancer and made remarkable postoperative improvement. The authors conclude that surgical treatment of solitary metastatic lesion may produce good symptomatic relief irrespective of patient's age and primary pathology, while emphasising the need for detailed clinical evaluation of patients with 'red flag' symptoms.

Objective: Given the likely proliferation of targeted testing and treatment strategies for cancer, a better understanding of the utilization patterns of human epidermal growth factor receptor 2 (HER2) testing and trastuzumab and newer gene expression profiling (GEP) for risk stratification and chemotherapy decision making are important., Study Design: Cross-sectional., Methods: We performed a medical record review of women aged 35 to 65 years diagnosed between 2006 and 2007 with invasive localized breast cancer, identified using claims from a large national health plan (N = 775)., Results: Almost all women received HER2 testing (96.9%), and 24.9% of women with an accepted indication received GEP. Unexplained socioeconomic differences in GEP use were apparent after adjusting for age and clinical characteristics; specifically, GEP use increased with income. For example, those in the lowest income category (<$40,000) were less likely than those with an income of $125,000 or more to receive GEP (odds ratio, 0.34; 95% confidence interval, 0.16 to 0.73). A majority of women (57.7%) with HER2-positive disease received trastuzumab; among these women, differences in age and clinical characteristics were not apparent, although surprisingly, those in the lowest income category were more likely than those in the high-income category to receive trastuzumab (P = .02). Among women who did not have a positive HER2 test, 3.9% still received trastuzumab. Receipt of adjuvant chemotherapy increased as GEP score indicated greater risk of recurrence., Conclusion: Identifying and eliminating unnecessary variation in the use of these expensive tests and treatments should be part of quality improvement and efficiency programs.

In a time-motion study conducted in a hospital that recently implemented barcode medication administration (BCMA) technology, we found that the BCMA system did not increase the amount of time nurses spend on medication administration activities, and did not compromise the amount of time nurses spent on direct care of patients. Our results should allay concerns regarding the impact of BCMA on nursing workflow.

Blood lymphocyte numbers, essential for the development of efficient immune responses, are maintained by recirculation through secondary lymphoid organs. We show that lymphocyte trafficking is altered by the lysophospholipid sphingosine-1-phosphate (S1P) and by a phosphoryl metabolite of the immunosuppressive agent FTY720. Both species were high-affinity agonists of at least four of the five S1P receptors. These agonists produce lymphopenia in blood and thoracic duct lymph by sequestration of lymphocytes in lymph nodes, but not spleen. S1P receptor agonists induced emptying of lymphoid sinuses by retention of lymphocytes on the abluminal side of sinus-lining endothelium and inhibition of egress into lymph. Inhibition of lymphocyte recirculation by activation of S1P receptors may result in therapeutically useful immunosuppression.

The chemokine receptors CCR5 and CXCR4 are co-receptors together with CD4 for human immunodeficiency virus (HIV)-1 entry into target cells. Macrophage-tropic HIV-1 viruses use CCR5 as a co-receptor, whereas T-cell-line tropic viruses use CXCR4. HIV-1 infects the brain and causes a progressive encephalopathy in 20 to 30% of infected children and adults. Most of the HIV-1-infected cells in the brain are macrophages and microglia. We examined expression of CCR5 and CXCR4 in brain tissue from 20 pediatric acquired immune deficiency syndrome (AIDS) patients in relation to neuropathological consequences of HIV-1 infection. The overall frequency of CCR5-positive perivascular mononuclear cells and macrophages was increased in the brains of children with severe HIV-1 encephalitis (HIVE) compared with children with mild HIVE or non-AIDS controls, whereas the frequency of CXCR4-positive perivascular cells did not correlate with disease severity. CCR5- and CXCR4-positive macrophages and microglia were detected in inflammatory lesions in the brain of children with severe HIVE. In addition, CXCR4 was detected in a subpopulation of neurons in autopsy brain tissue and primary human brain cultures. Similar findings were demonstrated in the brain of adult AIDS patients and controls. These findings suggest that CCR5-positive mononuclear cells, macrophages, and microglia contribute to disease progression in the central nervous system of children and adults with AIDS by serving as targets for virus replication.