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Budd-Chiari syndrome in small hepatic veins: A diagnostic and therapeutic challenge in a low resource setting.
No full textIntroduction
Budd-Chiari syndrome (BCS) is a rare condition affecting one in a million adults. BCS involves outflow obstruction in the hepatic venous system, which can occur anywhere between the small hepatic veins and the atrio-caval junction and cannot be due to heart, pericardial, or hepatic veno-occlusive disease.
Case Presentation
We report an exceedingly rare form of BCS with less common initial clinical features in a young poor adult male patient which ignited a diagnostic uncertainty and a therapeutic challenge. The presence of the classical triad of BCS in the absence of major hepatic vein obstruction prompted the medical team to consider that the patient had a rare form of BCS. In this case, the financial condition of the patient and limited resources available restricted our ability to advance into the specific investigations. However, the patient was given symptomatic medical treatment and was followed up monthly. We also provided the patient with a statement that reaffirmed our inability to provide affordable surgical management options and called for an optimized national clinical guideline that could help the physicians deal with the challenges.
Conclusion
An uncommon form of BCS in this patient provided a diagnostic challenge and therapeutic uncertainty in the low-resource settings. Primary care physicians should commence evidenced medical management based on clinical suspicion acknowledging the fact that obstruction of small hepatic veins is often not detected on an ultrasound
A systematic review and meta-analysis of interventions to preserve insulin-secreting beta cell function in people newly diagnosed with type 1 diabetes: results from intervention studies aimed at improving glucose control.
No full textAIMS
Type 1 diabetes is characterised by the destruction of pancreatic beta cells. Significant levels of beta cells remain at diagnosis. Preserving these cells improves glucose control and protects from long-term complications. We undertook a systematic review and meta-analyses of all randomised controlled trials (RCTs) of interventions to preserve beta cell function in people newly diagnosed with type 1 diabetes. This paper reports the results of interventions for improving glucose control to assess whether they preserve beta cell function.
METHODS
Searches for RCTs in MEDLINE, Embase, Cochrane CENTRAL, ClinicalTrials.gov and WHO International Clinical Trials Registry. Eligible studies included newly diagnosed type 1 diabetes patients, any intervention to improve glucose control and at least one month of follow-up. Data were extracted using a pre-defined data-extraction sheet with 10% of extractions checked by a second reviewer.
RESULTS
Twenty-eight studies with 1,662 participants were grouped by intervention into six subgroups (alternative insulins, subcutaneous and intravenous insulin delivery, intensive therapy, glucose sensing, adjuncts). Only three studies demonstrated an improvement in glucose control as well as beta cell function. These interventions included intensive insulin therapy and use of an alternative insulin.
CONCLUSIONS
This is the largest comprehensive review of RCTs in this area. It demonstrates a lack of robust evidence that interventions to improve glucose control preserve beta cell function in new onset type 1 diabetes, although analysis was hampered by low quality evidence and inconsistent reporting of studies. Development of guidelines to support the design of trials in this field is a priority
Genomic and Expression Analyses Define MUC17 and PCNX1 as Predictors of Chemotherapy Response in Breast Cancer.
No full textPoor-prognosis breast cancers are treated with cytotoxic chemotherapy, but often without any guidance from therapy predictive markers because universally accepted markers are not currently available. Treatment failure, in the form of recurrences, is relatively common. We aimed to identify chemotherapy predictive markers and resistance pathways in breast cancer. Our hypothesis was that tumor cells remaining after neoadjuvant chemotherapy (NAC) contain somatic variants causing therapy resistance, while variants present pre-NAC but lost post-NAC cause sensitivity. Whole-exome sequencing was performed on matched pre- and post-NAC cancer cells, which were isolated by laser microdissection, from 6 cancer cases, and somatic variants selected for or against by NAC were identified. Somatic variant diversity was significantly reduced after therapy ( < 0.05). MUC17 variants were identified in 3 tumors and were selected against by NAC in each case, while PCNX1 variants were identified in 2 tumors and were selected for in both cases, implicating the function of these genes in defining chemoresponse. knockdown of MUC17 or PCNX1 was associated with significantly increased or decreased chemotherapy sensitivity, respectively ( < 0.05), further supporting their roles in chemotherapy response. Expression was tested for predictive value in two independent cohorts of chemotherapy-treated breast cancers ( = 53, = 303). Kaplan-Meier analyses revealed that low MUC17 expression was significantly associated with longer survival after chemotherapy, whereas low PCNX1 was significantly associated with reduced survival. We concluded that therapy-driven selection of somatic variants allows identification of chemotherapy response genes. With respect to MUC17 and PCNX1, therapy-driven selection acting on somatic variants, knockdown data concerning drug sensitivity, and survival analysis of expression levels in patient cohorts all define the genes as mediators of and predictive markers for chemotherapy response in breast cancer
Whole-genome sequencing of a sporadic primary immunodeficiency cohort.
No full textPrimary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of-and interplay between-novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans
Associations between Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blocker Use, Gastrointestinal Symptoms, and Mortality among Patients with COVID-19.
No full textMen living through multiple miscarriages: protocol for a qualitative exploration of experiences and support requirements.
No full textINTRODUCTION
Up to 1 in 4 pregnancies and 1 in 20 subsequent pregnancies end in miscarriage. Despite such prevalence the psychosocial effects are often unrecognised and unsupported. In the absence of any biomedical sequelae among men such marginalisation may be intensified. Men living through multiple miscarriages may also find any grief or anxiety intensified by loss of hope for future parenthood, but robust qualitative studies of these experiences are limited. We aim to rectify the deficiency.
METHODS AND ANALYSIS
Our qualitative study will adopt the sounds of silence framework designed by Serrant-Green to hear the voices of populations possibly marginalised. We will listen and learn from 30 to 50 men with a history of two or more miscarriages. The research participants will be recruited from a recurrent miscarriage clinic at a large tertiary hospital in England, and from advertisements to be disseminated by the project sponsor and miscarriage charities.Individual telephone interviews supported by a semistructured discussion guide will be audio-recorded, transcribed and anonymised. The transcriptions and any field notes will be interpreted by the framework method of Ritchie and Lewis embedded within the sounds of silence framework. Tentative findings will be presented to research participants in face-to-face focus group discussion, to enable member synthesis to enhance authenticity. The focus group discussion will be audio-recorded, transcribed, anonymised and similarly interpreted to contribute to our final synthesis.
ETHICS AND DISSEMINATION
The protocol of this project received a favourable opinion from the West Midlands South Birmingham Research Ethics Committee (16/WM/0423). Results will be submitted for publication in peer-reviewed journals and at conferences, and disseminated via newsletters and social media of our clinical collaborators and miscarriage charities. Outputs are anticipated to inform future policy and practice in the management of multiple miscarriages.
TRIAL REGISTRATION NUMBER
ISRCTN 21828561
The cost of providing mechanical thrombectomy in the UK NHS: a micro-costing study.
No full textINTRODUCTION
The clinical efficacy and cost-effectiveness of mechanical thrombectomy (MT) for the treatment of large vessel occlusion stroke is well established, but uncertainty remains around the true cost of delivering this treatment within the NHS. The aim of this study was to establish the cost of providing MT within the hyperacute phase of care and to explore differences in resources used and costs across different neuroscience centres in the UK.
METHOD
This was a multicentre retrospective study using micro-costing methods to enable a precise assessment of the costs of MT from an NHS perspective. Data on resources used and their costs were collected from five UK neuroscience centres between 2015 and 2018.
RESULTS
Data were collected on 310 patients with acute ischaemic stroke treated with MT. The mean total cost of providing MT and inpatient care within 24 hours was £10,846 (95% confidence interval (CI) 10,527-11,165) per patient. The main driver of cost was MT procedure costs, accounting for 73% (£7,943; 95% CI 7,649-8,237) of the total 24-hour cost. Costs were higher for patients treated under general anaesthesia (£11,048; standard deviation (SD) 2,654) than for local anaesthesia (£9,978; SD 2,654), mean difference £1,070 (95% CI 381-1,759; p=0.003); admission to an intensive care unit (ICU; £12,212; SD 3,028) against for admission elsewhere (£10,179; SD 2,415), mean difference £2,032 (95% CI 1,345-2,719; p<0001).The mean cost within 72 hours was £12,440 (95% CI 10,628-14,252). The total costs for the duration of inpatient care before discharge from a thrombectomy centre was £14,362 (95% CI 13,603-15,122).
CONCLUSIONS
Major factors contributing to costs of MT for stroke include consumables and staff for intervention, use of general anaesthesia and ICU admissions. These findings can inform the reimbursement, provision and strategic planning of stroke services and aid future economic evaluations
Trends in aetiology, treatment and complications associated with diabetic ketoacidosis (DKA) - a 6-year study at a large tertiary care centre in the West Midlands, United Kingdom.
No full textEmpty mast cell syndrome: fallacy or fact?
No full textPost-anaphylaxis mast cell anergy (PAMA), commonly referred to as 'empty mast cell (MC) syndrome', is a state of temporary loss of cutaneous MC reactivity in the immediate aftermath of anaphylaxis. Data relating to this condition are sparse and the incidence rate is currently unknown. PAMA has been described only in a few published case reports in the context of hymenoptera venom allergy and perioperative anaphylaxis. Best practice guidelines regarding optimal timing for performing skin tests postanaphylaxis are largely based on expert opinion, and allergy work-up has been recommended after 4-6 weeks postanaphylaxis to avoid false-negative results.This article provides a review of clinical literature surrounding PAMA, critically evaluates intracellular events in MCs from in vitro data and hypothesises regarding plausible immune mechanisms. There are no published data to directly explain molecular mechanisms underlying this phenomenon. Although not evidence based, PAMA has been attributed to depletion of MC granules following anaphylaxis. It is also plausible that exposure to high allergen concentrations in anaphylaxis can induce a temporary shift in MCs towards dominance of inhibitory signalling pathways, thus contributing to a state of transient hyporesponsiveness observed in some patients. Other potential contributory factors for reduced MC reactivity include downregulation of FcεRI expression, cross-linking of FcεRI to the inhibitory, low-affinity IgG receptors and administration of pharmacotherapeutic agents for anaphylaxis treatment. It is likely that this interesting phenomenon can be explained by a combination of these proposed mechanisms in addition to other genetic/host factors that have not yet been identified
Phenotypic and functional translation of IL33 genetics in asthma.
No full textBACKGROUND
Asthma is a complex disease with multiple phenotypes that may differ in disease pathobiology and treatment response. Interleukin 33 (IL33) single nucleotide polymorphisms (SNPs) have been reproducibly associated with asthma. IL33 levels are elevated in sputum, and bronchial biopsies of asthma patients. The functional consequences of IL33 asthma SNPs remain unknown.
OBJECTIVE
We studied whether IL33 SNPs associate with asthma-related phenotypes and with IL33 expression in lung or bronchial epithelium. We investigated the effect of increased IL33 expression on human bronchial epithelial cell (HBEC) function.
METHODS
Association between IL33 SNPs (Chr9: 5,815,786-6,657,983) and asthma phenotypes (Lifelines/DAG/GASP cohorts) and between SNPs and expression (lung tissue, bronchial brushes, HBECs) was done using regression modelling. Lentiviral overexpression was used to study IL33 effects on HBECs.
RESULTS
161 SNPs spanning the IL33 region associated with one or more asthma phenotypes after correction for multiple testing. We report one main independent signal tagged by rs992969 associating with blood eosinophil levels, asthma and eosinophilic asthma. A second, independent signal tagged by rs4008366 presented modest association with eosinophilic asthma. Neither signal associated with FEV, FEV/FVC, atopy, and age of asthma onset. The two IL33 signals are expression quantitative loci (eQTLs) in bronchial brushes and cultured HBECs, but not in lung tissue. IL33 overexpression in vitro resulted in reduced viability and ROS-capturing of HBECs, without influencing epithelial cell count, metabolic activity or barrier function.
CONCLUSION
We identify IL33 as an epithelial susceptibility gene for eosinophilia and asthma, provide mechanistic insight, and implicate targeting of the IL33 pathway specifically in eosinophilic asthma