Search

Background The number and complexity of clinical trials is growing, making finding and accessing trials increasingly challenging. A key barrier to increasing recruitment efficiency is patients' low awareness of trials as an option. They rarely hear about trials from oncologists, unless these are based at a research center, which introduces trial population biases. Even if patients decide to search for trial information on their own, it is difficult for laypeople to understand. Trial search tools exist, but have multiple shortcomings: complex navigation, limited search functionality, data too complex for non-specialists, and next steps unclear. Methods Access to trials via a novel trial search tool using technology, including artificial intelligence (AI), to restructure trial information and match patients to trials was the focus of this study. We focused on 6 gastrointestinal cancers for evaluating the search tool's AI model in which their trial information was restructured based on key eligibility differentiators identified. Research participants were recruited with the support of patient associations leveraging social media. They were asked to complete a survey evaluating an established tool and the novel tool to find trials relevant for them. They assessed aspects of the tools' usability on 5-level Likert scales. Results Survey respondents had a base level of awareness of trials, with patient associations and the internet as leading information sources. The novel tool made it easier to find trials, led to an improvement in ease of understanding information presented and provided more clarity on what the next steps towards enrollment would be. Overall, this led to higher patient satisfaction. Conclusions Novel patient-focused tools can unlock trial access for all patients. Democratizing trial information will not only increase trial accrual, but also patient satisfaction while reducing disparities. This tool could also be of value for academic or community oncologists who face similar issues when navigating trials for patients.

Objective Somatic mutations in UBA1 cause a newly defined syndrome known as VEXAS (vacuoles, E1 enzyme, X-linked, autoinflammatory, somatic syndrome). More than 50% of patients currently identified as having VEXAS met diagnostic criteria for relapsing polychondritis (RP), but clinical features that characterize VEXAS within a cohort of patients with RP have not been defined. We undertook this study to define the prevalence of somatic mutations in UBA1 in patients with RP and to create an algorithm to identify patients with genetically confirmed VEXAS among those with RP. Methods Exome and targeted sequencing of UBA1 was performed in a prospective observational cohort of patients with RP. Clinical and immunologic characteristics of patients with RP were compared based on the presence or absence of UBA1 mutations. The random forest method was used to derive a clinical algorithm to identify patients with UBA1 mutations. Results Seven of 92 patients with RP (7.6%) had UBA1 mutations (referred to here as VEXAS-RP). Patients with VEXAS-RP were all male, were on average ≥45 years of age at disease onset, and commonly had fever, ear chondritis, skin involvement, deep vein thrombosis, and pulmonary infiltrates. No patient with VEXAS-RP had chondritis of the airways or costochondritis. Mortality was greater in VEXAS-RP than in RP (23% versus 4%; P = 0.029). Elevated acute-phase reactants and hematologic abnormalities (e.g., macrocytic anemia, thrombocytopenia, lymphopenia, multiple myeloma, myelodysplastic syndrome) were prevalent in VEXAS-RP. A decision tree algorithm based on male sex, a mean corpuscular volume >100 fl, and a platelet count

Background: Direct-acting antiviral (DAA) therapy for anybody with viraemic HCV infection has been scaled-up in England since 2017. To assess early impacts, we described trends in, and factors associated with, HCV viraemia among people who inject drugs (PWID). We also examined trends in self-reported treatment access.Methods: Bio-behavioural data from an annual, national surveillance survey of PWID (2011 to 2018) estimated trends in viraemic prevalence among HCV antibody-positive PWID. Multivariable logistic regression identified characteristics independently associated with viraemia. Trends in treatment access were examined for PWID with known infection.Findings: Between 2011 and 2016, viraemic prevalence among antibody-positive PWID remained stable (2011, 57.7%; 2016, 55.8%) but decreased in 2017 (49.4%) and 2018 (50.4%) (both p

In children, seizures represent an extremely heterogeneous group of medical conditions ranging from benign cases, such as a simple febrile seizure, to life-threatening situations, such as status epilepticus. Underlying causes of seizures also represent a wide range of pathologies from idiopathic cases, usually genetic, to a variety of acute and chronic intracranial or systemic abnormalities. This document discusses appropriate utilization of neuroimaging tests in a child with seizures. The clinical scenarios in this document take into consideration different circumstances at the time of a child's presentation including the patient's age, precipitating event (if any), and clinical and electroencephalogram findings and include neonatal seizures, simple and complex febrile seizures, post-traumatic seizures, focal seizures, primary generalized seizures in a neurologically normal child, and generalized seizures in neurologically abnormal child. This practical approach aims to guide clinicians in clinical decision-making and to help identify efficient and appropriate imaging workup. The American College of Radiology Appropriateness Criteria are evidence-based guidelines for specific clinical conditions that are reviewed annually by a multidisciplinary expert panel. The guideline development and revision include an extensive analysis of current medical literature from peer reviewed journals and the application of well-established methodologies (RAND/UCLA Appropriateness Method and Grading of Recommendations Assessment, Development, and Evaluation or GRADE) to rate the appropriateness of imaging and treatment procedures for specific clinical scenarios. In those instances where evidence is lacking or equivocal, expert opinion may supplement the available evidence to recommend imaging or treatment.

Cardiovascular disease (CVD) risk factors were examined among church leaders (n = 2309) who attended Mid-South United Methodist Church annual meetings between 2012 and 2017 using repeated cross-sectional data. There was a significant increase in body mass index (BMI) (b = 0.24, p = 0.001) and significant decreases in blood pressure (systolic: b = − 1.08, p

Pediatric seizures commonly trigger emergency medical services (EMS) activation and account for approximately 5-15% of all pediatric 911-EMS calls. More than 50% of children with active seizure activity do not receive prehospital antiepileptic drugs, potentially because they are not recognized by EMS. The purpose of this study is to evaluate specificity and sensitivity of paramedic identification of pediatric seizures and to describe the characteristics of unrecognized seizures.This is an 18-month prospective cohort study at a single, pediatric emergency department (ED). EMS patients ≤15 years old with a prehospital provider impression of seizure were included. Upon ED arrival, a data collection form, which included the EMS verbal report and patient's clinical status, was completed by the attending emergency physician. The primary outcome was sensitivity and specificity of paramedic identification of active seizure. Secondary outcomes included characteristics of missed seizures, ED interventions, and disposition. Descriptive statistics, sensitivity, and specificity were computed. Patient characteristics and clinical outcomes were compared.Surveys were completed for 349 patients (Median 3, IQR = 3.4). Fifty-two of the patients (15%) were actively seizing upon arrival at the ED. Sensitivity was 54% and specificity was 96% for paramedic identification of active seizure. Common features of missed cases were abnormal vital signs (75%), gaze deviation (50%) and clenched jaw (33%). Of these, 37% required intubation and 53% were admitted to the intensive care unit.Paramedics were highly specific, but not sensitive in identifying active seizures on ED arrival. Patients with unrecognized seizures presented most commonly with abnormal vital signs and gaze deviation.

Oral nutritional supplements may be prescribed for the management of disease-related malnutrition, but there is a large variety of nutritionally differing products available. ONS prescribing in primary care is an area of uncertainty for GPs and prescribing of ONS on the NHS in England and Wales in 2018/2019 was over £150000000. Clinically appropriate prescribing of oral nutritional supplements is supported by the use of validated malnutrition screening tools to assess the patient's risk of malnutrition. Local prescribing formularies promote the use of cost-effective oral nutritional supplements products in primary care which are often not available for use in secondary care. A new medicines management model of practice which uses pharmacy technicians, with clinical support from a dietitian, to address inappropriate oral nutritional supplements prescribing in primary care is described here. The model maximises the skills within the medicines management team and promotes a food first, aging-well approach to managing malnutrition in primary care.

PurposeThis study aimed to investigate the effectiveness of a specialist UK day treatment programme (DTP), in terms of whether improvements in eating disorder symptomology and psychosocial impairment achieved at discharge were maintained at 6-month and 12-month follow-ups.Design/methodology/approachA total of 69 patients (aged 16+) with eating disorders who had received treatment in the DTP were reviewed at 6-month and 12-month follow-ups, using demographic, physiological and psychological measures. Quantitative outcomes were analysed using one-way repeated measures analysis of variance.FindingsData analysis revealed that significant improvements in eating disordered attitudes, body mass index (among underweight participants), binge frequency (among participants with those symptoms) and psychosocial impairment achieved at discharge, were also maintained at 6-month and 12-month follow-ups, and with large effect sizes. All hypotheses were supported, with the exception that frequency of vomiting symptoms had deteriorated at the 12-month follow-up and was no longer significantly different from vomiting frequency on admission.Originality/valueResults provide support for the sustained effectiveness of DTPs in improving eating disorder symptoms and psychosocial impairment associated with eating disorders. This is the first study to evaluate the effectiveness of a UK DTP for adults at maintaining improvements to eating disorder symptoms and attitudes at follow-up.

Research on the acceptability of faith-based health promotion programs by Latino communities in the Bible Belt is limited. This study examined the needs, barriers, and facilitators related to such programs in Memphis, TN. Thirty Latino community members and ten faith leaders participated in focus groups and in-depth interviews, respectively. Health needs identified included diet, dental care, and screenings, while barriers included cost, education, lack of prevention-seeking behaviors, and need for Spanish language services. Faith leaders were aware of more health resources than community members. Despite being receptive and acknowledging the need for faith-based programs aimed at prevention and filling healthcare gaps, concerns regarding the influence of religious doctrine on health interventions were expressed by members of both groups. Faith leaders, practitioners, and community members must work together to overcome barriers related to trust and health behavior norms.

Early recognition and treatment of seizures is essential for optimal patient outcomes. Seizure activity, particularly in young children, can be subtle and often go unrecognized by providers. This case series retrospectively identified 7 cases of pediatric patients (14 years and younger) who presented to the emergency department with active seizure activity that was unrecognized by the prehospital care providers. The presentation of these patients, their clinical signs of seizure, and emergency department disposition are highlighted in this series.

Objective Tuberculosis (TB) can affect young children, resulting in serious disease at a young age or reactivation later in life. Identifying cases of latent TB infection (LTBI) in children exposed to active cases is important to prevent morbidity and mortality. There is currently limited guidance on appropriate testing methods in situations involving mass screening of children in low TB incidence settings such as England. This study describes case reports of two separate occasions in which nursery-age children in England underwent LTBI screening and explores the decisions involved in choosing the most appropriate test and screening process. Methods A literature search, review of health protection case and incident management notes, and interviews with key stakeholders were conducted. Results Two different tests—tuberculin skin testing and interferon gamma release assay—were used in each respective screening situation and the decision between the two was taken based on cohort, organizational, and index case risk factors. Screening took place in dedicated secondary care clinics. No cases of LTBI were identified from either screening incident. Conclusion Our study highlights the lack of definitive guidance for mass LTBI screening of young children and presents the approaches to decision making that can be adopted by others. Further research is required to test the approach suggested in this article and to ensure that evidence-based national guidance provides a consistent and effective approach to such incidents.

Total hip arthroplasty (THA) is a viable option to restore mobility and relieve pain in patients with severe post-tuberculous arthritis, but has been controversial due to concerns of disease reactivation. Over the past several decades, a number of authors have reported outcomes of THA for tuberculosis (TB) infections. However, there is marked heterogeneity in regard to disease activity, surgical approaches, and the use of chemoprophylaxis in these studies.The purpose of this review was to critically assess: 1) patient characteristics; 2) perioperative planning; 3) clinical outcomes; 4) radiographic outcomes; and 5) complications of THA in the setting of tuberculosis of the hip.THA is an effective treatment for post-TB hip arthritis. There has been controversy regarding its safety during the past several decades, as it has been thought to increase the risk of disease reactivation. While studies thus far have shown generally favorable results, they have been limited by small sample sizes and their design as retrospective case series. Comparison of these studies reveals marked heterogeneity in the clinical management of this complex disease. However, synthesis of their findings demonstrates favorable outcomes and low rates of complication, including disease reactivation particularly when perioperative anti-tuberculosis therapy is instituted.

Mouth and genital ulcers with inflamed cartilage (MAGIC) syndrome is characterized by overlapping features of relapsing polychondritis (RP) and Behcet's disease (BD). To date, no studies have defined the clinical spectrum of disease in a cohort of patients with MAGIC syndrome.Adult patients within an ongoing prospective, observational cohort study in RP were clinically assessed for MAGIC syndrome. A systematic review was conducted to identify additional cases of MAGIC syndrome by searching four databases: PubMed (US National Library of Medicine), Embase (Elsevier), Scopus (Elsevier) and Web of Science: Core Collection (Clarivate Analytics). The inclusion criteria used were: [1] patients of any age or gender who were diagnosed with MAGIC syndrome, or both RP and BD; [2] case report or case series study; [3] published from 1985 - July 2020; and [4] in English language. Risk of bias was assessed using a checklist developed by the authors and based on the Consensus-based Clinical Case Reporting (CARE) Guidelines. Search results screening, article inclusion, data extraction and risk of bais assessment was performed independently by two investigators. Clinical characteristics, particularly BD-related features, were compared between patients with MAGIC syndrome and cases of non-MAGIC RP. The performance characteristics of different criteria to classify MAGIC syndrome were also evaluated.Out of 96 patients with RP, 13 (14%) patients were diagnosed with MAGIC syndrome. For the systematic review, 380 articles were retrieved of which 90 were screened at title and abstract levels. Of these screened, 60 were excluded and 30 proceeded to full text review where an additional 8 were excluded. Twenty-two articles were included in our review and from which 27 additional cases of MAGIC syndrome were identified. Pooling all 40 cases together and comparing them with non-MAGIC RP, there was a significantly higher prevalence of ocular involvement (28% vs 4%, p0.01), cutaneous involvement (35% vs 1%, p0.01), GI involvement (23% vs 4%, p0.01), and CNS involvement (8% vs 0, p = 0.04) in MAGIC syndrome. A higher prevalence of aortitis (23% vs 1%, p0.01), Raynaud's phenomenon (54% vs 11%, p0.01), and elevated anti-collagen II antibodies (50% vs 9%, p = 0.04) were observed in MAGIC syndrome. Fulfillment of either McAdam's or Damiani's Criteria for RP plus the International Criteria for Behçet's Disease had excellent sensitivity (98%) to classify cases of MAGIC syndrome.A substantial proportion of patients with RP can be clinically diagnosed with MAGIC syndrome. These patients have features of RP, BD, and other unique features including aortitis, Raynaud's phenomenon and elevated anti-collagen II antibodies.

Supplemental Digital Content is available in the text., IMPORTANCE: Even with its proclivity for older age, coronavirus disease 2019 has been shown to affect all age groups. However, there remains a lack of research focused primarily on the young adult population. OBJECTIVES: To describe the epidemiology and outcomes of coronavirus disease 2019 and identify the risk factors associated with critical illness and mortality in hospitalized young adults. DESIGN, SETTINGS, AND PARTICIPANTS: A retrospective cohort study of the Society of Critical Care Medicine’s Viral Infection and Respiratory Illness Universal Study registry. Patients 18–40 years old, hospitalized from coronavirus disease 2019 from March 2020 to April 2021, were included in the analysis. MAIN OUTCOMES AND MEASURES: Critical illness was defined as a composite of mortality and 21 predefined interventions and complications. Multivariable logistic regression was used to assess associations with critical illness and mortality. RESULTS: Data from 4,005 patients (152 centers, 19 countries, 18.6% non-U.S. patients) were analyzed. The median age was 32 years (interquartile range, 27–37 yr); 51% were female, 29.4% Hispanic, and 42.9% had obesity. Most patients (63.2%) had comorbidities, the most common being hypertension (14.5%) and diabetes (13.7%). Hospital and ICU mortality were 3.2% (129/4,005) and 8.3% (109/1,313), respectively. Critical illness occurred in 25% (n = 996), and 34.3% (n = 1,376) were admitted to the ICU. Older age (p = 0.03), male sex (adjusted odds ratio, 1.83 [95% CI, 1.2–2.6]), and obesity (adjusted odds ratio, 1.6 [95% CI, 1.1–2.4]) were associated with hospital mortality. In addition to the above factors, the presence of any comorbidity was associated with critical illness from coronavirus disease 2019. Multiple sensitivity analyses, including analysis with U.S. patients only and patients admitted to high-volume sites, showed similar risk factors. CONCLUSIONS: Among hospitalized young adults, obese males with comorbidities are at higher risk of developing critical illness or dying from coronavirus disease 2019.

The opioid crisis has greatly affected not only adults but also children as well. As clinicians develop effective approaches to minimize pain and distress in children, the risks and benefits of opioids must be carefully considered. Children of parents with opioid use disorder are also at risk of living in unstable environments, performing poorly academically, engaging in future drug use, and having increased stress, which affects their development before entering adulthood. This statement focuses on the effects of the opioid crisis on children and adolescents and is intended to inform institutional policies, improve education, advocate for evidence‐informed guidelines, and improve the care of children affected by the opioid epidemic who are seen in the emergency department.

Objectives Relapsing polychondritis (RP) is a rare, heterogeneous, systemic inflammatory disease that targets cartilage. Patient-reported outcome measures may differ from physician assessment. This study compared patient global assessment (PtGA) and physician global assessment (PhGA) scores in a prospective cohort of patients with RP. Methods Adult patients with RP underwent a standardized comprehensive evaluation at ∼6 month intervals. At each visit, three physicians scored PhGA by consensus. The patient independently completed four patient-reported outcomes: PtGA, 36-item Short Form Health Survey (SF-36), Brief Illness Perception Questionnaire (BIPQ) and Multidimensional Fatigue Inventory (MFI). Patient–physician discordance was defined as a difference between PtGA and PhGA of ≥3 on a 0–10 scale. Results A total of 76 patients were evaluated over 154 visits. The median PhGA was 3 [interquartile range (IQR) 2–3] and the median PtGA was 5 (IQR 4–7). PtGA and PhGA were concordant in 66 visits (42.9%) and patients scored disease severity ≥3 points higher than physicians scored disease activity (positive discordance) in 84 visits (54.5%). Compared with visits with concordance, visits with positive discordance were associated with significantly worse scores on the MFI, BIPQ, SF-36 physical component score and SF-36 mental component score. Conclusion Patients with RP typically self-report high PtGA that does not align with PhGA. Discordance is likely driven by the high physical and psychological burden of illness experienced by patients. Multifaceted treatment approaches that address the burden of disease in RP from the patient perspective are needed.

Background/Aims Statins are associated with muscle symptoms, from myalgia with normal CK, to rhabdomyolysis. A sub-group have an autoimmune necrotising myopathy with anti-3-hydroxy-3-methylglutaryl-coenzyme A reductase (anti-HMGCR) antibodies. This can present variably, from mild self-limiting illness to severe myopathy unresponsive to statin withdrawal, requiring long-term immunosuppression. A study from New Zealand estimated the incidence of anti-HMGCR-associated myositis to be 1 in 90,000 statin users, and an incidence of 1 in 500,000 has been estimated in a US population. Anti-HMGCR antibodies were first reported in 2010. As they are new, and testing is not widely available, they may be under-recognised in the routine assessment of patients with myopathies. However, detection is important as prompt immunosuppression may be needed. Methods We compared the 2019 incidence of anti-HMGCR antibodies in Southern England from two different laboratory groups, utilising different testing criteria. The St George’s and Berkshire Surrey Pathology Services (StG/BSPS) laboratories serve a population of 3.25 million and test anti-HMGCR antibodies solely on clinician request. The Southampton laboratory serves a population of 2.33 million and tests anti-HMGCR as part of the immunoblot for all myositis-associated antibodies and where clinical details suggest myositis or ILD. Results In 2019, 14 tests were performed by StG/BSPS and 662 by Southampton, with anti-HMGCR positives of 5 (36%) and 28 (4.2%) respectively. Adjusted to include only the adult population, the incidence of anti-HMGCR antibodies is 1 in 514,000 in the StG/BSPS area versus 1 in 66,000 in the Southampton area. We estimate statins to be used in 308,000 adults in the StG/BSPS and in 220,000 in the Southampton areas, assuming treatment in 12% of adults and age demographics representative of the national population. This suggests an incidence of anti-HMGCR antibodies of approximately 1 in 62,000 statin users in the StG/BSPS area and 1 in 8,000 statin users in the Southampton area, though statin exposure was not confirmed in all positive cases. Preliminary data from 17 anti-HMGCR positive cases shows that 76% had taken statins, for an average duration of 5.84 years (range 0.75-16 years). Median peak CK was 6489 (range 241-27555). 76% required immunosuppression, of which 70% required two or more different treatments. Conclusion The 7.7-fold higher incidence from the Southampton laboratory reflects a proactive approach, selecting far more samples for anti-HMGCR assessment than specifically requested by clinicians. This demonstrates under-awareness of this antibody in routine care. We propose adoption of an algorithm to trigger more widespread testing for anti-HMGCR antibodies, to identify cases amongst those with statin-associated myalgia or myositis, and in others without statin exposure. This will lead to better understanding of the spectrum of clinical disease associated with anti-HMGCR antibodies, as well as early detection and treatment of those who develop a necrotising myopathy. Disclosure V.M.K. Joseph: None. E.C. Rose: None. M. Lloyd: None. C.J. Edwards: None. S.K. Amar: None. T. Forster: None. K.A. Smith: None. R.D. Wheeler: None. P.D.W. Kiely: None.

Objective To describe the impact of the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) pandemic on people who inject drugs (PWID) in England, Wales and Northern Ireland. Study design Cross-sectional unlinked anonymous monitoring (UAM) Survey of PWID. Methods People who had ever injected psychoactive drugs were recruited to the UAM Survey by specialist drug/alcohol services in England, Wales and Northern Ireland. From June 2020, in addition to providing a dried blood spot sample and completing the UAM behavioural questionnaire, participants were asked to complete an enhanced coronavirus disease (COVID-19) questionnaire. Preliminary data are presented to the end of October and were compared to data from the 2019 UAM Survey, where possible. Results Between June and October, 288 PWID were recruited from England and Northern Ireland. One in nine (11%; 29/260) PWID reported testing positive for SARS-CoV-2 or experiencing COVID-19 symptoms. Fifteen percent (26/169) reported injecting more frequently in 2020 compared to 2019; cocaine injection in the preceding four weeks increased from 17% (242/1,456) to 25% (33/130). One in five PWID (22%; 35/188) reported difficulties in accessing HIV and hepatitis testing and one in four (26%; 47/179) reported difficulties in accessing equipment for safer injecting. Conclusions Our preliminary findings suggest that PWID have experienced negative impacts on health, behaviours and access to essential harm reduction, testing and treatment services due to the COVID-19 pandemic. Continued monitoring through surveillance and research is needed to understand the subsequent impact of COVID-19 on blood-borne virus transmission in this population and on health inequalities., Highlights • People who inject drugs (PWID) in England/Northern Ireland are at risk of COVID-19. • Patterns of psychoactive drug use have shifted over the course of the pandemic. • Of particular concern, access to essential services for PWID have been restricted.

Purpose To evaluate the effectiveness of an adaptation of Interpersonal Group Psychotherapy (IPT-G), in facilitating short- and longer-term improvements in eating disorder symptomology, psychosocial impairment, anxiety, depression and attachment difficulties among adults living with overweight and diagnosed with binge eating disorder (BED). Design/methodology/approach In total, 24 participants completed measures at the start of IPT-G, mid-treatment, discharge and six-month follow-up. Quantitative outcomes were analysed utilising one-way repeated measures analysis of variance. Findings Treatment retention was 100%. Significant improvements in binge-eating frequency, psychosocial impairment and depression were achieved at mid-treatment and maintained at post-treatment and six-month follow-up, and with large effect sizes. Attachment anxiety had reduced significantly at post-treatment and was maintained at six-month review. Body mass index (BMI) had stabilised by mid-treatment and was maintained at post-treatment and six-month follow-up. All hypotheses were supported, with the exception that attachment avoidance did not improve significantly and following a post-treatment reduction, anxiety symptoms deteriorated slightly by six-month follow-up, such that they were no longer significantly different from pre-treatment levels. Practical implications Despite being the most prevalent of the eating disorders (compared to anorexia nervosa and bulimia nervosa), BED is under-recognised and under-treated in clinical settings. Results indicate the sustained effectiveness of IPT-G in improving eating disorder and comorbid symptomology associated with BED. Originality/value This is the first UK study to investigate the effectiveness of IPT-G at treating BED. Unlike previous studies in the field, this study did not exclude participants based on age, BMI or psychiatric comorbidity.

Large-scale genetic studies revealed SCN2A as one of the most frequently mutated genes in patients with neurodevelopmental disorders. SCN2A encodes for the voltage-gated sodium channel isoform 1.2 (Nav 1.2) expressed in the neurons of the central nervous system. Homozygous knockout (null) of Scn2a in mice is perinatal lethal, whereas heterozygous knockout of Scn2a (Scn2a+/- ) results in mild behavior abnormalities. The Nav 1.2 expression level in Scn2a+/- mice is reported to be around 50-60% of the wild-type (WT) level, which indicates that a close to 50% reduction of Nav 1.2 expression may not be sufficient to lead to major behavioral phenotypes in mice. To overcome this barrier, we characterized a novel mouse model of severe Scn2a deficiency using a targeted gene-trap knockout (gtKO) strategy. This approach produces viable homozygous mice (Scn2agtKO/gtKO ) that can survive to adulthood, with about a quarter of Nav 1.2 expression compared to WT mice. Innate behaviors like nesting and mating were profoundly disrupted in Scn2agtKO/gtKO mice. Notably, Scn2agtKO/gtKO mice have a significantly decreased center duration compared to WT in the open field test, suggesting anxiety-like behaviors in a novel, open space. These mice also have decreased thermal and cold tolerance. Additionally, Scn2agtKO/gtKO mice have increased fix-pattern exploration in the novel object exploration test and a slight increase in grooming, indicating a detectable level of repetitive behaviors. They bury little to no marbles and have decreased interaction with novel objects. These Scn2a gene-trap knockout mice thus provide a unique model to study pathophysiology associated with severe Scn2a deficiency.

Summary Background Congenital anomalies are the fifth leading cause of mortality in children younger than 5 years globally. Many gastrointestinal congenital anomalies are fatal without timely access to neonatal surgical care, but few studies have been done on these conditions in low-income and middle-income countries (LMICs). We compared outcomes of the seven most common gastrointestinal congenital anomalies in low-income, middle-income, and high-income countries globally, and identified factors associated with mortality. Methods We did a multicentre, international prospective cohort study of patients younger than 16 years, presenting to hospital for the first time with oesophageal atresia, congenital diaphragmatic hernia, intestinal atresia, gastroschisis, exomphalos, anorectal malformation, and Hirschsprung's disease. Recruitment was of consecutive patients for a minimum of 1 month between October, 2018, and April, 2019. We collected data on patient demographics, clinical status, interventions, and outcomes using the REDCap platform. Patients were followed up for 30 days after primary intervention, or 30 days after admission if they did not receive an intervention. The primary outcome was all-cause, in-hospital mortality for all conditions combined and each condition individually, stratified by country income status. We did a complete case analysis. Findings We included 3849 patients with 3975 study conditions (560 with oesophageal atresia, 448 with congenital diaphragmatic hernia, 681 with intestinal atresia, 453 with gastroschisis, 325 with exomphalos, 991 with anorectal malformation, and 517 with Hirschsprung's disease) from 264 hospitals (89 in high-income countries, 166 in middle-income countries, and nine in low-income countries) in 74 countries. Of the 3849 patients, 2231 (58·0%) were male. Median gestational age at birth was 38 weeks (IQR 36–39) and median bodyweight at presentation was 2·8 kg (2·3–3·3). Mortality among all patients was 37 (39·8%) of 93 in low-income countries, 583 (20·4%) of 2860 in middle-income countries, and 50 (5·6%) of 896 in high-income countries (p

OBJECTIVE Relapsing polychondritis (RP) is a systemic inflammatory disorder of cartilage that lacks validated disease activity measures. Physician global assessment (PhGA), a measure of disease activity commonly used in rheumatologic diseases, has not been tested in a cohort of patients with RP. METHODS Adult patients in an observational cohort of RP underwent standardized, comprehensive evaluation at approximately 6-month intervals. PhGA was scored by three physicians from the evaluating institution on a scale of 0 to 10 for each visit. A random subset of twenty visits was scored by three, independent physicians not affiliated with the evaluating institution. Treatment change between consecutive visits was categorized as increased, decreased or unchanged. RESULTS 78 patients were evaluated over 164 visits. The interclass correlation coefficient (ICC) (2, 1) for the three raters from the evaluating institution was excellent (0.79, 95% CI: 0.73-0.84) but was poor in the subset of cases scored by the additional raters (ICC (2,1) = 0.27, 95% CI: -0.01-0.53). Median PhGA was 3 (range 0-7). PhGA weakly correlated with CRP (rs = 0.30, p< 0.01). In response to increased treatment, median PhGA decreased from 3 (IQR: 2-4) to 2 (IQR: 2-3) (p< 0.01) but rarely went to 0. CONCLUSION Within a single-center, PhGA can be used to quantify disease activity and monitor disease response in RP. Persistent disease activity despite treatment, rather than a relapsing-remitting pattern, is observed for most patients with RP. Reliability of PhGA may not generalize across different institutions. A validated disease-specific activity index is needed in RP.

Painful diagnostic and therapeutic procedures are common in the emergency department. Adequately treating pain, including the pain of procedures is an essential component of the practice of emergency medicine. Pain management is also part of the core competency for emergency medicine residencies and pediatric emergency medicine fellowships. There are many benefits to providing local and/or topical anesthesia before performing a medical procedure, including better patient and family satisfaction and increased procedural success rates. Local and topical anesthetics when used appropriately, generally, have few, if any, systemic side effects, such as hypotension or respiratory depression, which is an advantage over procedural sedation. Use of local and topical anesthetics can do much toward alleviating the pain and anxiety of pediatric patients undergoing procedures in the emergency department.

Severe acute respiratory syndrome coronavirus (SARS-CoV-2), the virus causing Coronavirus disease 2019 (COVID-19), has had a huge impact on health services with a high mortality associated with complications including pneumonia and acute respiratory distress syndrome. Historical evidence suggests that Lupus patients have a higher incidence of several viral infections. This is likely due to a combination of immune dysfunction, immunosuppressive therapy and excess co-morbidities. In this context there has been concern that Lupus patients may be at a higher risk of developing COVID-19 and suffering a severe disease course. As a result, many Lupus patients have been advised to ‘shield’ by isolating from social contact in the hope that this will reduce the likelihood of infection. Early clinical data does not appear to show that the incidence of COVID-19 is higher in Lupus patients. Reassuringly, the clinical course of COVID-19 in Lupus does not generally seem to be more severe than in the general population. There has been huge interest in repurposing existing drugs as potential treatments, including several used to treat Lupus. Of these, corticosteroids and hydroxychloroquine are the most well researched so far. The current evidence suggests that the corticosteroid dexamethasone improves outcome for the sickest COVID-19 patients requiring respiratory support. Initial reports suggested that hydroxychloroquine could have a positive impact on the course of COVID-19, however larger prospective studies have not supported this. Janus kinase inhibitors, currently being investigated for efficacy in lupus, have been shown to have anti-viral effects in vitro and inhibiting the JAK-STAT pathway may dampen down the host hyper-inflammatory response. Several trials are ongoing to assess the outcome of the use of JAK inhibitors in COVID-19 positive patients. For most patients continuing with their existing therapies to prevent a lupus flare or adverse events associated with sudden corticosteroid withdrawal is important whilst an Individualised risk assessment remains vital.

Stroke is a leading cause of childhood mortality. Moreover, stroke survivors are at risk of persistent neurological deficits, seizures, and stroke recurrence. Venous thromboembolism most commonly refers to deep vein thrombosis and pulmonary embolism, although it can occur anywhere in the vascular system, including the renal and portal circulation systems. Hypertensive emergency is defined as acute severe hypertension with target organ damage or life-threatening features. Pediatric stroke, venous thromboembolism, and hypertensive emergencies occur less frequently in children than in adults. The underlying pathophysiology is significantly different in children. Despite differences between children and adults in risk factors and contributing factors, treatment is often extrapolated from adult management. This chapter reviews common and atypical presentations of these disorders, the approach to diagnostic confirmation, as well as important management principles.

Fever is common in children, and serious etiologies with significant sequelae must be identified and treated. This chapter discusses the classic and atypical presentations of several important pediatric infectious disease conditions, including bacterial and viral meningitis (inflammation of the meninges that typically occurs in response to an infectious process), infectious encephalitis (inflammation of the brain parenchyma that presents clinically with neurologic dysfunction), retropharyngeal abscess (a potentially life-threatening airway emergency secondary to an infection of the retropharyngeal soft tissue space), and cat scratch disease secondary to Bartonella henselae infection (an infectious lymphadenopathy after exposure to cats or cat fleas). Diagnostic confirmation and treatment of these conditions are also discussed.

Respiratory emergencies are common in children, and emergency providers must anticipate respiratory compromise and intervene early. Respiratory emergencies can be broadly categorized into upper and lower respiratory diseases. Sometimes the diagnosis is classic and easily made based on history and confirmed by key physical examination findings. Other times, the diagnosis can be more challenging to confirm, and there may be presentation overlap. This chapter discusses the classic and atypical presentation of many important pediatric respiratory conditions, including croup, bronchiolitis, pneumonia, asthma, epiglottitis, bacterial tracheitis, and anaphylaxis. Key diagnostic features and aids to differentiating the disease from common mimics are emphasized.

BackgroundThe European Centre for Disease Prevention and Control, National Institute for Health and Care Excellence and Public Health England have all endorsed the use of antivirals for the treatment and prophylaxis of influenza for care home residents. However, implementing these guidelines in practice is often challenging. This article aims to explore what factors impact the management of care home flu outbreaks in England according to national guidelines and highlight opportunities for change.MethodsQualitative data from notified outbreaks between September 2017 to April 2018 in the South East of England were analyzed, applying the Greenhalgh framework for barriers to guideline implementation. Summary statistics on outbreak characteristics were generated. Stakeholders were mapped out using Eden and Ackermann’s grid of interest and influence. A process map was developed to describe operational pathways.ResultsThere was often a delay in notifying potential outbreaks to Public Health England. Clinicians cited a lack of robust evidence for the use of antivirals and the available guidelines being too unwieldy as reasons for not implementing prescribing guidance. Many high interests and high influence stakeholders are involved in the sometimes complex care pathway, requiring coordinated work and agreement before antivirals can be prescribed.ConclusionsOur findings highlight points in the care pathway that stakeholders can target to improve quality of care and increase the likelihood of national guidance being implemented. The principles described in this article can also be applied to other challenges of translating evidence into practice and cross-organisational working.

Sarcoidosis is a systemic inflammatory disease characterized by development of granulomas in the affected organs. Sarcoidosis is often a diagnosis of exclusion, and traditionally used tests for sarcoidosis demonstrate low sensitivity and specificity. We propose that accuracy of diagnosis can be improved if biomarkers of altered lymphocyte populations and levels of signaling molecules involved in disease pathogenesis are measured for patterns suggestive of sarcoidosis. These distinctive biomarkers can also be used to determine disease progression, predict prognosis, and make treatment decisions. Many subsets of T lymphocytes, including CD8+ T-cells and regulatory T-cells, have been shown to be dysfunctional in sarcoidosis, and the predominant CD4+ T helper cell subset in granulomas appears to be a strong indicator of disease phenotype and outcome. Studies of altered B cell populations, B cell signaling molecules, and immune complexes in sarcoidosis patients reveal promising biomarkers as well as possible explanations of disease etiology. Furthermore, examined biomarkers raise questions about new treatment methods and sarcoidosis antigens.

Recent large-scale genomic studies have revealedSCN2Aas one of the most frequently mutated gene in patients with neurodevelopmental disorders including autism spectrum disorder and intellectual disability.SCN2Aencodes for voltage-gated sodium channel isoform 1.2 (Nav1.2), which is mainly expressed in the central nervous system and responsible for the propagation of neuronal action potentials. Homozygous knockout (null) ofScn2ais perinatal lethal, whereas heterozygous knockout ofScn2aresults in mild behavior abnormalities. To achieve a more substantial, but not complete, reduction ofScn2aexpression, we characterized aScn2adeficient mouse model using a targeted gene trap knockout (gtKO) strategy to recapitulate loss-of-functionSCN2Adisorders. This model produces viable homozygous mice (Scn2agtKO/gtKO) that can survive to adulthood, with markedly low but detectable Nav1.2 expression. AlthoughScn2agtKO/gtKOadult mice possess normal olfactory, taste, hearing, and mechanical sensitivity, they have decreased thermal and cold tolerance. Innate behaviors are profoundly impaired including impaired nesting, marble burying, and mating. These mice also have increased food and water intake with subsequent increases in fecal excretion of more but smaller fecal boli. This novelScn2agene trap knockout mouse thus provides a unique model to study pathophysiology associated withScn2adeficiency.

Objective: This study examined diabetes knowledge, health fatalism (the belief that health outcomes are outside one’s control), and their interaction, as predictors of Type 2 Diabetes preventive be...

This is a revision of the previous joint Policy Statement titled “Guidelines for Care of Children in the Emergency Department.” Children have unique physical and psychosocial needs that are heightened in the setting of serious or life-threatening emergencies. The majority of children who are ill and injured are brought to community hospital emergency departments (EDs) by virtue of proximity. It is therefore imperative that all EDs have the appropriate resources (medications, equipment, policies, and education) and capable staff to provide effective emergency care for children. In this Policy Statement, we outline the resources necessary for EDs to stand ready to care for children of all ages. These recommendations are consistent with the recommendations of the Institute of Medicine (now called the National Academy of Medicine) in its report “The Future of Emergency Care in the US Health System.” Although resources within emergency and trauma care systems vary locally, regionally, and nationally, it is essential that ED staff, administrators, and medical directors seek to meet or exceed these recommendations to ensure that high-quality emergency care is available for all children. These updated recommendations are intended to serve as a resource for clinical and administrative leadership in EDs as they strive to improve their readiness for children of all ages.

Posterior oropharyngeal trauma commonly occurs in children and frequently presents to the emergency department (ED). Rarely, serious infectious and neurologic sequelae result. Emergency providers are tasked with the challenge of diagnosing the minority with life-threatening complications while maintaining thoughtful stewardship regarding radiation exposure. A previously healthy 2-year-old girl sustained trauma to her posterior oropharynx with a toothbrush that resulted in a left carotid dissection. This dissection was diagnosed in the ED via computed tomography angiogram, Otolaryngology and neurosurgery were consulted in the ED, and anticoagulation therapy was initiated with aspirin. The child did initially well and was without neurologic deficit and no brain ischemia on magnetic resonance imaging. She was discharged home on aspirin therapy. Four days after initial injury, the child returned to the ED after a seizure. Computed tomography scan of the head demonstrated infarction at the junction of the left parietal and temporal areas. Although neurologic complications are rare, posterior oropharyngeal trauma in children is not. There are many diagnostic and therapeutic challenges in its management. This case is, to the authors' awareness, the first case report in the English literature of a known and treated carotid dissection in a child after posterior oropharyngeal trauma that resulted in stroke despite diagnosis and initiation of treatment. The diagnostic and therapeutic challenges of posterior oropharyngeal trauma in children are discussed in this article.

Uncertainty regarding the excess of mortality in patients treated with clozapine persists. A decrease in all-cause mortality, and perhaps also in suicide, after clozapine initiation has been reported, but there are no studies in which preventable causes were ascertained in those taking medication in the long term. Here, we aimed to assess a decade of causes of deaths in a catchment area in patients with schizophrenia chronically treated with clozapine and compared them to a clozapine-treated control cohort. Causes of deaths were classified as suicide, expected (e.g. cancer), and unexpected deaths (encompassing causes of death potentially due to clozapine side effects, and unexplained sudden death). We used descriptive statistics for comparing socio-demographic and clinical factors between the three groups. Logistic regression models were used to examine risk factors associated with unexpected death compared to the control group. We found that the overall mortality was similar to that in previous studies (at 0.8% yearly on average) with unexpected deaths accounting for 52% of total deaths. The unexpected deaths group was on average treated with higher clozapine doses (mean 460 mg/day). A small but significant peak of unexpected deaths was found during the 2018 summer heat wave, which might have exacerbated dose-dependent side effects of clozapine. We suggest increased monitoring for those on higher doses of clozapine as one potential intervention to decrease mortality in this population.

Preconditioning tissue with sublethal ischaemia or hypoxia can confer tolerance (protection) against subsequent ischaemic challenge. In vitro ischaemic preconditioning (IPC) is typically achieved through oxygen glucose deprivation (OGD), whereas hypoxic preconditioning (HPC) involves oxygen deprivation (OD) alone. Here, we report the effects of preconditioning of OGD, OD or glucose deprivation (GD) in ischaemic tolerance models with PC12 cells and primary rat neurons. PC12 cells preconditioned (4 h) with GD or OGD, but not OD, prior to reperfusion (24 h) then ischaemic challenge (OGD 6 h), showed greater mitochondrial activity, reduced cytotoxicity and decreased apoptosis, compared to sham preconditioned PC12 cells. Furthermore, 4 h preconditioning with reduced glucose (0.565 g/L, reduced from 4.5 g/L) conferred protective effects, but not for higher concentrations (1.125 or 2.25 g/L). Preconditioning (4 h) with OGD, but not OD or GD, induced stabilization of hypoxia inducible factor 1α (HIF1α) and upregulation of HIF1 downstream genes (Vegf, Glut1, Pfkfb3 and Ldha). In primary rat neurons, only OGD preconditioning (4 h) conferred neuroprotection. OGD preconditioning (4 h) induced stabilization of HIF1α and upregulation of HIF1 downstream genes (Vegf, Phd2 and Bnip3). In conclusion, OGD preconditioning (4 h) followed by 24 h reperfusion induced ischaemic tolerance (against OGD, 6 h) in both PC12 cells and primary rat neurons. The OGD preconditioning protection is associated with HIF1α stabilization and upregulation of HIF1 downstream gene expression. GD preconditioning (4 h) leads to protection in PC12 cells, but not in neurons. This GD preconditioning-induced protection was not associated with HIF1α stabilization.

© 2018 John Wiley & Sons, Ltd. Objective: Successful biologic disease-modifying anti-rheumatic drug (bDMARD) dose reduction appears increasingly possible from clinical trials. The present study aimed to understand the patient perspective of bDMARD dose reduction. Methods: Patients with rheumatoid arthritis, ankylosing spondylitis or psoriatic arthritis who were self-administering subcutaneous bDMARDs therapy at two National Health Service trusts participated in semi-structured interviews. To capture multiple experiences, patients were purposefully sampled for a range of age, gender, disease duration, reducing/not reducing bDMARDs and either within 3–12months of bDMARD initiation or ≥12months and in remission/low disease activity. Inductive thematic analysis was utilized. Results: Fifteen patients were interviewed (six on dose reduction). Five overarching themes were identified. When thinking about dose reduction, patients reflected on their difficult life before bDMARDs (“Where I was then”) compared with their transformative effects (“Where I am now”). All raised concerns that a dose reduction would take them back to where they used to be (“Fears for the future”) and most believed it to be a cost-cutting exercise. Most had “Hopes for the future”, that a reduction would lower their risk of side effects, and release funds for other patients. They wanted a clear rationale for reduction, collaborative decision making, and control over flexible dosing (“Information needs”). Conclusion: Patients were fearful of reducing the dose of their bDMARDs, having previously experienced uncontrollable symptoms. However, most were willing to try, provided that there was a clear rationale and that it was in their best interests, with opportunities for collaboration and dose control. These patient perspectives will inform the provision of patient information to guide clinical discussions.

TB of the knee is often associated with marked morbidity because of its late and non-specific presentation. The use of TKA (total knee arthroplasty) in the face of a previous tuberculous knee infection has been criticized with multiple controversies. Therefore, the purpose of this review is to assess: (1) clinical outcomes, (2) radiographic outcomes, and (3) complications of TKA in the face of a previous healed TB infection. Our analysis has demonstrated that previous TB infection of the knee joint does not preclude TKA if indicated and suggests placing patients who have ESR or CRP results out of normal range on pre-operative anti-TB prophylactic antibiotic for a minimum of 2 weeks. In case of local recurrence following TKA, antibiotic therapy alone can be an effective treatment option.We examined reported outcomes of performing TKA in patients with previous TB infection of the knee. Different strategies recommended by different authors to maximize the success of TKA in this situation are also discussed.TKA has been proven to be effective in patients who are status post tuberculous arthritis when thoughtful patient selection and peri-operative planning is conducted. Tuberculosis continues to have a rising incidence and increasing spread of multi-drug resistant strains.