Insulin Pump Therapy vs Multiple Daily Insulin Injections for Glycemic Control in Children With Type 1 Diabetes: A Systematic Review and Meta-Analysis.

Type 1 diabetes mellitus (T1DM), characterized by the autoimmune destruction of pancreatic beta cells and consequent insulin deficiency, leads to various complications. Management primarily focuses on optimal glycemic control through intensive insulin therapy, either via multiple daily injections (MDI) or continuous subcutaneous insulin infusion (CSII) using insulin pumps, which offer flexibility and improved basal insulin delivery. Despite the benefits of insulin pumps, such as reduced hypoglycemia risk and better mealtime insulin management, they pose challenges such as complexity in site changes and potential ketoacidosis due to tubing issues. This systematic review adheres to PRISMA guidelines and compares CSII with MDI in children and adolescents with T1DM, concentrating on outcomes such as glycemic control measured with HbA1c and glucose levels. The review includes studies meeting stringent criteria, encompassing a broad range of methodologies and geographies. The findings of this meta-analysis indicate the differences in glycemic control with CSII compared to MDI. However, significant heterogeneity in results and methodological variations across studies necessitate cautious interpretation. The study underscores the potential of CSII in offering better control for some patients, supporting a more personalized approach to T1DM management. It highlights the need for further research to understand the long-term effects and to refine treatment protocols, considering the variations in healthcare systems, treatment approaches, and patient demographics globally.

Impact of Silymarin Supplements on Liver Enzyme Levels: A Systematic Review.

Silymarin, extracted from milk thistle (Silybum marianum), is esteemed for its antioxidative, anti-inflammatory, and antifibrotic properties, notably within liver-related contexts. Nevertheless, a comprehensive grasp of its effects on liver enzymes remains elusive. This systematic review aims to scrutinize the influence of silymarin supplements on liver enzyme levels, elucidating its potential for hepatoprotection. Following PRISMA 2020 guidelines, we systematically reviewed pertinent studies in PubMed/MEDLINE (Medical Literature Analysis and Retrieval System Online). Our inclusion criteria comprised randomized clinical trials (RCTs) published between 1992 and 2023, accessible in English, with a primary focus on liver enzyme levels. Non-original research, ambiguously defined studies, and those lacking essential data were excluded. Of the 1,707 initially identified articles, 29 RCTs met the inclusion criteria, encompassing 3,846 participants with diverse underlying conditions. Silymarin dosages ranged from 140 mg to 420 mg, administered for various durations. Results revealed that 65.5% of the studies reported reduced liver enzyme levels, 20.7% exhibited no significant change, and 13.8% observed elevated liver enzymes. The systematic review implies a potential advantageous influence of silymarin on liver enzyme levels, indicating its hepatoprotective potential. Nevertheless, outcome disparities may stem from comorbidities, suboptimal doses, and underlying diseases. Notably, silymarin's impact on liver enzymes could be context-dependent, with varying responses among different conditions, with the decrease of liver enzyme levels in patients with non-alcoholic fatty liver disease. Silymarin supplements exhibit potential for hepatoprotection by ameliorating liver enzyme levels across diverse conditions. Further research should ascertain optimal dosages and contexts, accounting for individual patient characteristics and underlying diseases.

Comparison of Safety of Leadless Pacemakers and Transvenous Pacemakers: A Meta-Analysis.

Pacemakers have been accessible for six decades, and clearly defined criteria for pacemaker implantation have been established. Within the contemporary clinical practice, two dependable pacing platforms exist leadless pacemakers and transvenous pacemakers. The aim of this meta-analysis is to compare the safety of leadless pacemakers to transvenous pacemakers. This meta-analysis adhered to the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) 2020 framework. A comprehensive and systematic search was conducted across various databases including Scopus, Cochrane Library, and EMBASE, spanning from inception to August 15, 2023. The primary outcomes assessed in this meta-analysis were total complications, all-cause mortality, and device-related complications. Furthermore, secondary outcomes evaluated encompassed the need for reintervention, occurrences of pneumothorax, pericardial effusion, endocarditis, hemothorax, and hematoma. Total 17 studies were included in this meta-analysis. The findings of this study showed that patients with leadless pacemakers had a lower risk of total complications, device-related complications, pneumothorax, and endocarditis. The risk of reintervention was significantly lower in the leadless pacemaker group. However, compared to a transvenous pacemaker, the risk of pericardial effusion was significantly higher in the leadless pacemaker group. It is important to acknowledge the limitations arising from the lack of extensive long-term follow-up data for leadless pacemakers. As technology evolves, continued research will be essential in uncovering the full spectrum of prolonged complications associated with these devices.

Comparison of Immediate Versus Staged Complete Revascularisation in Patients Presenting With Acute Coronary Syndrome and Multivessel Disease: A Meta-Analysis of Randomized and Non-randomized Studies.

Acute myocardial infarction is a critical medical condition that poses a significant health burden, leading to substantial morbidity. Despite advancements in medical care, managing this condition is challenging for patients and society. The preferred approach appears to be comprehensive multivessel revascularization, yet the optimal timing remains uncertain. This study aims to compare immediate complete revascularisation and stage complete vascularization in patients presenting with acute coronary syndrome (ACS) and multivessel coronary artery disease (MVD). The Preferred Reporting of Systematic Reviews and Meta-analysis (PRISMA) guidelines conducted the present meta-analysis. A comprehensive literature search was conducted using online databases, including PubMed, and EMBASE from 2010 onwards, to identify articles that compared cardiovascular outcomes between patients undergoing immediate and staged complete revascularization. We also searched Google Scholar for additional studies relevant to the present meta-analysis. The primary outcome assessed in this study was major adverse cardiovascular events (MACE). Secondary outcomes included all-cause mortality, cardiovascular mortality, myocardial infarction (MI), and revascularization. A total of 15 studies fulfilled pre-defined eligibility criteria and were included in the final analysis. Our analysis shows that staged revascularization is associated with improved outcomes in patients with ACS and multivessel CAD, including all-cause mortality and cardiovascular mortality, without increasing the risk of major adverse cardiovascular events, myocardial infarction, and the need for unplanned revascularization.

Evaluation of the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in infantile epilepsy (Gene-STEPS): an international, multicentre, pilot cohort study.

BACKGROUND: Most neonatal and infantile-onset epilepsies have presumed genetic aetiologies, and early genetic diagnoses have the potential to inform clinical management and improve outcomes. We therefore aimed to determine the feasibility, diagnostic yield, and clinical utility of rapid genome sequencing in this population. METHODS: We conducted an international, multicentre, cohort study (Gene-STEPS), which is a pilot study of the International Precision Child Health Partnership (IPCHiP). IPCHiP is a consortium of four paediatric centres with tertiary-level subspecialty services in Australia, Canada, the UK, and the USA. We recruited infants with new-onset epilepsy or complex febrile seizures from IPCHiP centres, who were younger than 12 months at seizure onset. We excluded infants with simple febrile seizures, acute provoked seizures, known acquired cause, or known genetic cause. Blood samples were collected from probands and available biological parents. Clinical data were collected from medical records, treating clinicians, and parents. Trio genome sequencing was done when both parents were available, and duo or singleton genome sequencing was done when one or neither parent was available. Site-specific protocols were used for DNA extraction and library preparation. Rapid genome sequencing and analysis was done at clinically accredited laboratories, and results were returned to families. We analysed summary statistics for cohort demographic and clinical characteristics and the timing, diagnostic yield, and clinical impact of rapid genome sequencing. FINDINGS: Between Sept 1, 2021, and Aug 31, 2022, we enrolled 100 infants with new-onset epilepsy, of whom 41 (41%) were girls and 59 (59%) were boys. Median age of seizure onset was 128 days (IQR 46-192). For 43 (43% [binomial distribution 95% CI 33-53]) of 100 infants, we identified genetic diagnoses, with a median time from seizure onset to rapid genome sequencing result of 37 days (IQR 25-59). Genetic diagnosis was associated with neonatal seizure onset versus infantile seizure onset (14 [74%] of 19 vs 29 [36%] of 81; p=0·0027), referral setting (12 [71%] of 17 for intensive care, 19 [44%] of 43 non-intensive care inpatient, and 12 [28%] of 40 outpatient; p=0·0178), and epilepsy syndrome (13 [87%] of 15 for self-limited epilepsies, 18 [35%] of 51 for developmental and epileptic encephalopathies, 12 [35%] of 34 for other syndromes; p=0·001). Rapid genome sequencing revealed genetic heterogeneity, with 34 unique genes or genomic regions implicated. Genetic diagnoses had immediate clinical utility, informing treatment (24 [56%] of 43), additional evaluation (28 [65%]), prognosis (37 [86%]), and recurrence risk counselling (all cases). INTERPRETATION: Our findings support the feasibility of implementation of rapid genome sequencing in the clinical care of infants with new-onset epilepsy. Longitudinal follow-up is needed to further assess the role of rapid genetic diagnosis in improving clinical, quality-of-life, and economic outcomes. FUNDING: American Academy of Pediatrics, Boston Children's Hospital Children's Rare Disease Cohorts Initiative, Canadian Institutes of Health Research, Epilepsy Canada, Feiga Bresver Academic Foundation, Great Ormond Street Hospital Charity, Medical Research Council, Murdoch Children's Research Institute, National Institute of Child Health and Human Development, National Institute for Health and Care Research Great Ormond Street Hospital Biomedical Research Centre, One8 Foundation, Ontario Brain Institute, Robinson Family Initiative for Transformational Research, The Royal Children's Hospital Foundation, University of Toronto McLaughlin Centre.

A Rare Case of Kartagener Syndrome Presenting with Sinusitis, Situs Inversus, and Bronchiectasis: Emphasizing Early Diagnosis and Management Strategies.

Primary ciliary dyskinesia (PCDs), a subset of ciliary motility disorders, includes the rare hereditary illness Kartagener syndrome (KS). Sinusitis, situs inversus, and bronchiectasis, brought on by aberrant ciliary activity, are its defining features. We describe a case of an 18-year-old female with a history of recurrent respiratory complaints and chronic sinusitis. Additional testing confirmed the diagnosis of KS by identifying situs inversus, chronic bronchiectasis, and nasal polyps. This instance emphasizes the value of prompt KS diagnosis and treatment to avoid consequences. Supportive pulmonary care, antibiotics, and chest physical therapy are frequently employed, despite the lack of therapeutic standards. To further understand and manage this illness, more research is required. Patients with recurrent respiratory infections and structural lung disease can identify KS early.

A Case Report of Acute Severe Necrotizing Pancreatitis following the Johnson & Johnson Vaccine against the Novel SARS-CoV-2.

Acute pancreatitis is an inflammatory condition, which is a leading gastrointestinal cause of hospitalization in the United States. Several conditions are associated with acute pancreatitis. More recently, there have been a few cases reported of acute pancreatitis following the Pfizer-BioNTech COVID-19 mRNA vaccine. To our knowledge, no cases of acute pancreatitis have been yet reported following the Johnson & Johnson's Janssen COVID-19 vaccine (J& J vaccine). Herein we report a 34-year-old male with no significant past medical history admitted with acute necrotizing pancreatitis, the day following the receipt of the J&J vaccine. Based on the Naranjo and the modified Naranjo scale, the patient met the requirements for probable drug induced pancreatitis. This case report has the objective to raise awareness of a potentially severe side effect of the J&J vaccine. We hope to use this case to support screening all patients for previous history of acute pancreatitis before administration of the J& J vaccine.

Trio RNA sequencing in a cohort of medically complex children.

Genome sequencing (GS) is a powerful test for the diagnosis of rare genetic disorders. Although GS can enumerate most non-coding variation, determining which non-coding variants are disease-causing is challenging. RNA sequencing (RNA-seq) has emerged as an important tool to help address this issue, but its diagnostic utility remains understudied, and the added value of a trio design is unknown. We performed GS plus RNA-seq from blood using an automated clinical-grade high-throughput platform on 97 individuals from 39 families where the proband was a child with unexplained medical complexity. RNA-seq was an effective adjunct test when paired with GS. It enabled clarification of putative splice variants in three families, but it did not reveal variants not already identified by GS analysis. Trio RNA-seq decreased the number of candidates requiring manual review when filtering for de novo dominant disease-causing variants, allowing for the exclusion of 16% of gene-expression outliers and 27% of allele-specific-expression outliers. However, clear diagnostic benefit from the trio design was not observed. Blood-based RNA-seq can facilitate genome analysis in children with suspected undiagnosed genetic disease. In contrast to DNA sequencing, the clinical advantages of a trio RNA-seq design may be more limited.

Pharmacogenetic profiling via genome sequencing in children with medical complexity.

BACKGROUND: Children with medical complexity (CMC) are a priority pediatric population, with high resource use and associated costs. Genome-wide sequencing is increasingly organized for CMC early in life as a diagnostic test. Polypharmacy becomes common as CMC age. Clinically relevant pharmacogenetic (PGx) information can be extracted from existing genome sequencing (GS) data via GS-PGx profiling. The role of GS-PGx profiling in the CMC population is unclear. METHODS: Prescribed medications were extracted from care plans of 802 eligible CMC enrolled in a structured Complex Care Program over a 10-year period. Drug-gene associations were annotated using curated Clinical Pharmacogenetics Implementation Consortium data. GS-PGx profiling was then performed for a subset of 50 CMC. RESULTS: Overall, 546 CMC (68%) were prescribed at least one medication with an established PGx association. In the GS-PGx subgroup, 24 (48%) carried variants in pharmacogenes with drug-gene guidelines for one or more of their current medications. All had findings of potential relevance to some medications, including 32 (64%) with variants in CYP2C19 that could affect their metabolism of proton-pump inhibitors. CONCLUSION: GS-PGx profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of CMC. IMPACT: Polypharmacy and genetic test utilization are both common in children with medical complexity. The role of repurposing genome sequencing data for pharmacogenetic profiling in children with medical complexity was previously unclear. We identified a high rate of medication use with clinically relevant drug-gene associations in this priority pediatric population and demonstrated that relevant pharmacogenetic information can be extracted from their existing genome sequencing data. Pharmacogenetic profiling at the time of diagnostics-focused genetic testing could be an efficient way to incorporate precision prescribing practices into the lifelong care of children with medical complexity.

Variant-specific changes in RAC3 function disrupt corticogenesis in neurodevelopmental phenotypes.

Variants in RAC3, encoding a small GTPase RAC3 which is critical for the regulation of actin cytoskeleton and intracellular signal transduction, are associated with a rare neurodevelopmental disorder with structural brain anomalies and facial dysmorphism. We investigated a cohort of 10 unrelated participants presenting with global psychomotor delay, hypotonia, behavioural disturbances, stereotyped movements, dysmorphic features, seizures and musculoskeletal abnormalities. MRI of brain revealed a complex pattern of variable brain malformations, including callosal abnormalities, white matter thinning, grey matter heterotopia, polymicrogyria/dysgyria, brainstem anomalies and cerebellar dysplasia. These patients harboured eight distinct de novo RAC3 variants, including six novel variants (NM_005052.3): c.34G > C p.G12R, c.179G > A p.G60D, c.186_188delGGA p.E62del, c.187G > A p.D63N, c.191A > G p.Y64C and c.348G > C p.K116N. We then examined the pathophysiological significance of these novel and previously reported pathogenic variants p.P29L, p.P34R, p.A59G, p.Q61L and p.E62K. In vitro analyses revealed that all tested RAC3 variants were biochemically and biologically active to variable extent, and exhibited a spectrum of different affinities to downstream effectors including p21-activated kinase 1. We then focused on the four variants p.Q61L, p.E62del, p.D63N and p.Y64C in the Switch II region, which is essential for the biochemical activity of small GTPases and also a variation hot spot common to other Rho family genes, RAC1 and CDC42. Acute expression of the four variants in embryonic mouse brain using in utero electroporation caused defects in cortical neuron morphology and migration ending up with cluster formation during corticogenesis. Notably, defective migration by p.E62del, p.D63N and p.Y64C were rescued by a dominant negative version of p21-activated kinase 1. Our results indicate that RAC3 variants result in morphological and functional defects in cortical neurons during brain development through variant-specific mechanisms, eventually leading to heterogeneous neurodevelopmental phenotypes.

FISH analysis of brain smears obtained at intraoperative diagnosis - An accurate and fast method to detect 1p/19q-codeletion in gliomas.

The importance of molecular testing of gliomas is highlighted in the 2016 revised 4th edition of the WHO Classification of Tumours of the Central Nervous System, which applies an integrated diagnosis of histological and molecular features. In this classification system, oligodendrogliomas (ODG) are defined as IDH-mutant and 1p/19q-codeleted. Fluorescence in situ hybridization (FISH) analysis of formalin-fixed paraffin-embedded (FFPE) tissue is a standard method of determining 1p/19q-codeletion. However, it has several disadvantages, including requiring lengthy pretreatment, truncation artefact and lack of on-site access in many centers. In an effort to address these issues, we analysed FISH performed on smears obtained at intraoperative frozen section on 51 gliomas and compared this to FISH performed on subsequent FFPE sections. Four cases were excluded due to uninterpretable FISH results. Of the remaining 47 cases, 17 were concordant for 1p/19q-codeletion, 29 were concordant for lack of 1p/19q-codeletion, and 1 was discordant with 1p/19q-codeletion found on FFPE tissue but not on intraoperative smears. The discordant case was most likely due to sampling error, as the frozen section had not shown definite tumor. The FISH results on intraoperative smears were received within 24-48 h after the sample was collected, compared with 3-4 days for FFPE tissue. FISH on smears obtained at intraoperative frozen section is an accurate and fast method for determining 1p/19q-codeletion.

Comparison Of Anaesthetic Efficacy Of Articaine And Lidocaine In Nonsurgical Endodontic Treatment Of Permanent Mandibular Molars With Symptomatic Irreversible Pulpitis. A Randomized Clinical Trial.

BACKGROUND: Inferior Alveolar Nerve Block (IANB) with Buccal Infiltration (BI) anaesthesia is required to completely anesthetize the mandibular molars with symptomatic irreversible pulpitis. 4% Articaine and 2% Lidocaine provide local anaesthesia during the nonsurgical endodontic treatment of mandibular molars with symptomatic irreversible pulpitis. Objective of the study was to compare the effect of Articaine and Lidocaine in the combination of Inferior alveolar nerve block with buccal infiltration anaesthesia during the nonsurgical endodontic treatment of mandibular molars with symptomatic Irreversible Pulpitis. METHODS: One hundred and sixty participants with Symptomatic Irreversible Pulpitis of permanent mandibular molars were divided randomly in two groups. Group A was given Articaine 4% IANB along with BI whereas group B was given Lidocaine 2%. Pain was assessed after 15 minutes of administration of local anaesthesia. Anaesthetic success of the agents is defined as, absence of pain or mild pain first during the access cavity preparation then instrumentation of the canals of tooth. Chi-square test was applied to analyse data for statistical significance. RESULTS: Anaesthetic success of Articaine was 96.2% during access cavity preparation compared to Lidocaine (86.2%). Success during instrumentation of canals was also found to be high in Articaine (90.2%) compared to Lidocaine (76.2%). This difference of anaesthetic efficacy between Articaine and Lidocaine was found statistically significant. (p=0.02). CONCLUSIONS: Articaine is found to be better than Lidocaine regarding anaesthetic efficacy and hence, it can be a safer alternative to Lidocaine.

Genome sequencing for detection of pathogenic deep intronic variation: A clinical case report illustrating opportunities and challenges.

Variants in JAM3 have been reported in four families manifesting a severe autosomal recessive disorder characterized by hemorrhagic destruction of the brain, subependymal calcification, and cataracts. We describe a 7-year-old male with a similar presentation found by research-based quad genome sequencing to have two novel splicing variants in trans in JAM3, including one deep intronic variant (NM_032801.4: c.256+1260G>C) not detectable by standard exome sequencing. Targeted sequencing of RNA isolated from transformed lymphoblastoid cell lines confirmed that each of the two variants has a deleterious effect on JAM3 mRNA splicing. The role for genome sequencing as a clinical diagnostic test extends to those patients with phenotypes strongly suggestive of a specific Mendelian disorder, especially when the causal genetic variant(s) are not found by a more targeted approach. Barriers to diagnosis via identification of pathogenic deep intronic variation include lack of laboratory consensus regarding in silico splicing prediction tools and limited access to clinically validated confirmatory RNA experiments.

Effect of Delayed-Release and Extended-Release Methylphenidate on Caregiver Strain and Validation of Psychometric Properties of the Caregiver Strain Questionnaire: Results from a Phase 3 Trial in Children with Attention-Deficit/Hyperactivity Disorder.

Objectives: Inadequately controlled symptoms and associated impaired functioning have a significant negative impact on caregivers of children with attention-deficit/hyperactivity disorder (ADHD). This study aimed to assess the impact of evening-dosed, delayed-release and extended-release methylphenidate (DR/ER-MPH) treatment on caregiver strain, measured by the Caregiver Strain Questionnaire (CGSQ), and present post hoc psychometric analyses assessing the reliability and validity of the CGSQ, its ability to detect change (responsiveness), and to derive responder definitions. Methods: The CGSQ was an exploratory efficacy endpoint in a phase 3, 3-week, randomized, double-blind, multicenter, placebo-controlled, forced-dose titration trial of DR/ER-MPH in children aged 6-12 years with ADHD (NCT02520388). Psychometric properties of the CGSQ evaluated post hoc included internal consistency using Cronbach's alpha; test/retest reliability using intraclass correlation coefficients (ICCs); construct validity (known groups and convergent/divergent validity); responsiveness to changes in assessments of ADHD severity (ADHD Rating Scale-IV [ADHD-RS-IV], Conners' Global Index-Parent [CGI-P], and Clinical Global Impression-Severity [CGI-S]/CGI-Improvement [CGI-I]); and meaningful change threshold (MCT) using receiver operating characteristic curves, which were used to compare response between DR/ER-MPH and placebo groups. Results: Randomized DR/ER-MPH (54.5) and placebo (54.9) groups had similar mean CGSQ scores at screening. Caregivers of children on DR/ER-MPH reported significant reductions in CGSQ scores after 3 weeks of DR/ER-MPH treatment versus placebo (least-squares mean: 41.2 vs. 49.1; p < 0.001). The CGSQ demonstrated strong internal consistency (Cronbach's alpha = 0.93) and good test/retest reliability (ICC = 0.72). Known groups, convergent/divergent validity, and responsiveness were demonstrated from relationships between the CGSQ and the CGI-S, ADHD-RS-IV, and CGI-P. The mean anchor-based MCT for CGSQ total score was estimated as -9.0 (DR/ER-MPH vs. placebo: 53.2% vs. 29.9% p = 0.003). Conclusions: CGSQ scores significantly decreased after 3 weeks of DR/ER-MPH treatment versus placebo, and the CGSQ was found to be a valid and reliable measure of strain in caregivers of children with ADHD. Clinical trial registration identification number: NCT02520388.

The value of endomyocardial biopsy in diagnosis and guiding therapy.

Endomyocardial biopsy (EMB) is a highly-specialised procedure that is associated with some controversy as to its diagnostic role due to its inconsistency in diagnosing a wide variety of cardiac diseases. Given the advances and sophistication in echocardiography and cardiac magnetic resonance imaging (MRI), the vast majority of cardiac diseases can be diagnosed by these non-invasive procedures. Under-sampling and the fact that biopsy site is limited to the right side of the interventricular septum further limits its value. In spite of all these limitations, there still remains a group of pathological conditions that require biopsy for a conclusive diagnosis such as myocarditis, amyloidosis, sarcoidosis and giant cell myocarditis. Correct patient selection and the quantity of tissue samples impart a significant influence on the accuracy of the diagnosis, and thus the value of EMB is variable for each patient. The purpose of this study was to evaluate the role of EMB in patient care, through its ability to either change clinical diagnosis or alter patient management. Our study was based in a single teaching centre. An audit of cardiac biopsies performed over a 10 year period identified 250 patients. We assessed indications, histology, electron microscopic findings, final clinical diagnosis and how they influenced patient management. A definite diagnosis on histology was given in 44 of 250 patients (17.6%). Non-specific findings were observed in the remaining 206 patients (82.4%). Histology influenced patient management in 73 (29.2%) patients. Histological examination in the remaining 177 biopsies (70.8%) did not provide a definite diagnosis or influence patient management. It was additionally found that the number of tissue fragments sampled has significant impact on diagnostic accuracy. A more accurate diagnosis of 45% was obtained when ≥5 fragments were sampled, as compared to 1-3 fragments where accuracy dropped to 20%. Our study indicated that sampling for electron microscopy has very limited value. We found that of 245 biopsies sampled for electron microscopy, only three biopsies (1.2%) had diagnostically useful findings. In our institution procedure related complications were observed in 7 of 250 patients (2.8%). The diagnostic value of EMB is important but limited. Strict triaging of patients according to clinical suspicion and adequate sampling of tissue may increase useful diagnostic information.

Predicting discordant HER2 results in ipsilateral synchronous invasive breast carcinomas: experience from a single institution.

With the emergence of multiple lines of highly effective Human Epidermal Growth Factor Receptor 2 (HER2) directed therapy, accurate identification of HER2 positive tumour has become a critical aspect in the histopathological analysis of breast cancers. Multifocal invasive breast carcinomas are relatively common, and given the aggressive inherent biology of HER2 positive disease, identification of even small tumours with HER2 positive status may be of importance for treatment planning. There are currently no clear guidelines as to whether all of these foci should be tested for HER2 status. We reviewed the results of 172 patients in whom HER2 in situ hybridisation (ISH) testing was performed on at least two ipsilateral synchronous invasive carcinomas. Discordant results in different invasive foci were relatively uncommon and occurred in only eight (5%) of the 172 patients. This showed a statistically significant correlation with similarly discordant oestrogen receptor (ER) results. In addition HER2 discordance was more likely amongst different tumour foci if these arose in distinct and separate areas of DCIS. An algorithm based on a combination of College of American Pathologists (CAP) recommendation for HER2 testing, differing ER status and background DCIS profile may be useful in detecting these discordant cases.

Self-monitoring of oral anticoagulation: systematic review and meta-analysis of individual patient data.

BACKGROUND: Uptake of self-testing and self-management of oral anticoagulation [corrected] has remained inconsistent, despite good evidence of their effectiveness. To clarify the value of self-monitoring of oral anticoagulation, we did a meta-analysis of individual patient data addressing several important gaps in the evidence, including an estimate of the effect on time to death, first major haemorrhage, and thromboembolism. METHODS: We searched Ovid versions of Embase (1980-2009) and Medline (1966-2009), limiting searches to randomised trials with a maximally sensitive strategy. We approached all authors of included trials and requested individual patient data: primary outcomes were time to death, first major haemorrhage, and first thromboembolic event. We did prespecified subgroup analyses according to age, type of control-group care (anticoagulation-clinic care vs primary care), self-testing alone versus self-management, and sex. We analysed patients with mechanical heart valves or atrial fibrillation separately. We used a random-effect model method to calculate pooled hazard ratios and did tests for interaction and heterogeneity, and calculated a time-specific number needed to treat. FINDINGS: Of 1357 abstracts, we included 11 trials with data for 6417 participants and 12,800 person-years of follow-up. We reported a significant reduction in thromboembolic events in the self-monitoring group (hazard ratio 0·51; 95% CI 0·31-0·85) but not for major haemorrhagic events (0·88, 0·74-1·06) or death (0·82, 0·62-1·09). Participants younger than 55 years showed a striking reduction in thrombotic events (hazard ratio 0·33, 95% CI 0·17-0·66), as did participants with mechanical heart valve (0·52, 0·35-0·77). Analysis of major outcomes in the very elderly (age ≥85 years, n=99) showed no significant adverse effects of the intervention for all outcomes. INTERPRETATION: Our analysis showed that self-monitoring and self-management of oral coagulation is a safe option for suitable patients of all ages. Patients should also be offered the option to self-manage their disease with suitable health-care support as back-up. FUNDING: UK National Institute for Health Research (NIHR) Technology Assessment Programme, UK NIHR National School for Primary Care Research.

APOE genotype makes a small contribution to warfarin dose requirements.

Alterations in vitamin K availability can significantly influence anticoagulation response to warfarin. Apolipoprotein E (APOE) plays a part in the hepatic uptake of lipid-soluble vitamin K. This study aimed to determine the influence of common polymorphisms in the APOE gene on warfarin dose requirements. patients with stable anticoagulation control and with a target International Normalized Ratio (INR) 2.0-3.0 were genotyped for the APOE epsilon2, epsilon3 and epsilon4 variants. Mean +/- SD daily warfarin doses were significantly lower in patients carrying at least one epsilon4 allele compared to the epsilon3epsilon3 reference genotype (3.3 +/- 1.9 versus 4.0 +/- 1.8; P = 0.03; 95% CI: 0.1-1.2). Multivariate regression analysis showed that patient age, height and CYP2C9, VKORC1 and APOE genotypes significantly contributed to warfarin dose requirement (R = 57%). only the epsilon4 allele of APOE was found to make a significant (P = 0.002) but small contribution to warfarin dose requirement. There was no significant difference in fasted plasma vitamin K concentration between patients with the different APOE genotypes. This study suggests that APOE genotype is unlikely to have a clinically significant effect on warfarin dose requirements.