A blockchain-based framework to support pharmacogenetic data sharing.

The successful implementation of pharmacogenetics (PGx) into clinical practice requires patient genomic data to be shared between stakeholders in multiple settings. This creates a number of barriers to widespread adoption of PGx, including privacy concerns related to the storage and movement of identifiable genomic data. Informatic solutions that support secure and equitable data access for genomic data are therefore important to PGx. Here we propose a methodology that uses smart contracts implemented on a blockchain-based framework, PGxChain, to address this issue. The design requirements for PGxChain were identified through a systematic literature review, identifying technical challenges and barriers impeding the clinical implementation of pharmacogenomics. These requirements included security and privacy, accessibility, interoperability, traceability and legal compliance. A proof-of-concept implementation based on Ethereum was then developed that met the design requirements. PGxChain's performance was examined using Hyperledger Caliper for latency, throughput, and transaction success rate. The findings clearly indicate that blockchain technology offers considerable potential to advance pharmacogenetic data sharing, particularly with regard to PGx data security and privacy, large-scale accessibility of PGx data, PGx data interoperability between multiple health care providers and compliance with data-sharing laws and regulations.

Hypoglycaemia represents a clinically significant manifestation of PIK3CA- and CCND2-associated segmental overgrowth.

The PI3K-AKT signalling cascade has a highly conserved role in a variety of processes including cell growth and glucose homoeostasis. Variants affecting this pathway can lead to one of several segmental overgrowth disorders. These conditions are genetically heterogeneous and require tailored, multidisciplinary involvement throughout life. Hypoglycaemia is common in other overgrowth syndromes but has been described only sporadically in association with PIK3CA and CCND2 variants. We report a cohort of 6 children with megalencephaly-capillary malformation (MCAP) and megalencephaly-polydactyly-polymicrogyria-hydrocephalus (MPPH) syndromes who developed clinically significant hypoglycaemia. Based on our findings, we suggest that segmental overgrowth patients should be screened for low blood glucose levels during childhood and there should be early specialist endocrine review in any children who develop hypoglycaemia.

A case-control study examining inconsistencies in pain management following fractured neck of femur: an inferior analgesia for the cognitively impaired.

Previous research suggests individuals who suffer from cognitive impairment are less able to vocalise pain than the rest of the cognitively-intact population. This feature of cognitive impairment may be leading to a chronic underdetection of pain as current assessment tools strongly rely on the participation of the patient. To explore inconsistencies in pain management within the acute setting, we conducted a retrospective assessment of 224 patients presenting with fractured neck of femur at a large teaching hospital's accident and emergency (A&E) department between 2 June 2011 and 2 June 2012. These patients were split into either a cognitively-impaired or cognitively-intact cohort based on their Abbreviated Mental Test Scores. Patients with cognitive impairment, on average, received a weaker level of analgesia than individuals without impairment both in the ambulance and in A&E. In the ambulance, 45% of cognitively-impaired patients were prescribed no pain relief compared with just 8% of those individuals who remain cognitively intact. After arrival at A&E, these inconsistencies continued with 69% of the cognitively-intact cohort receiving the strongest opioid analgesia compared with just 37% of the cognitively-impaired cohort. The cognitively-impaired cohort would also wait on average an hour longer before receiving this initial pain relief. We believe that these differences stem from cognitively-impaired patients being unable to vocalise their pain through traditional assessment methods. This work discusses the potential development or adoption of a tool which can be applied in the acute setting and relies less on vocalisation but more on the objective features of pain, so making it applicable to cognitively-impaired individuals.

Central serous chorioretinopathy secondary to intramuscular testosterone therapy.

Summary: A patient treated with intramuscular testosterone replacement therapy for primary hypogonadism developed blurred vision shortly after receiving his testosterone injection. The symptom resolved over subsequent weeks and recurred after his next injection. A diagnosis of central serous chorioretinopathy (CSR) was confirmed following ophthalmology review. A decision was made to change the patient's testosterone regime from this 12-weekly intramuscular injection to a daily topical testosterone gel, given the possibility that peak blood levels of testosterone following intramuscular injection were causing his ocular complaint. His CSR did not recur after this change in treatment. CSR secondary to testosterone therapy is a rare finding but has been reported previously in the literature. Learning Points: Blurred vision in patients treated with testosterone replacement therapy (TRT) should prompt an ophthalmology review. The potential for reduced risk of central serous chorioretinopathy (CSR) with daily transdermal testosterone remains a matter of conjecture. CSR is a rare potential side effect of TRT.

Acute diabetic neuropathy following improved glycaemic control: a case series and review.

SUMMARY: We present three cases of acute diabetic neuropathy and highlight a potentially underappreciated link between tightening of glycaemic control and acute neuropathies in patients with diabetes. Case 1: A 56-year-old male with poorly controlled type 2 diabetes (T2DM) was commenced on basal-bolus insulin. He presented 6 weeks later with a diffuse painful sensory neuropathy and postural hypotension. He was diagnosed with treatment-induced neuropathy (TIN, insulin neuritis) and obtained symptomatic relief from pregabalin. Case 2: A 67-year-old male with T2DM and chronic hyperglycaemia presented with left lower limb pain, weakness and weight loss shortly after achieving target glycaemia with oral anti-hyperglycaemics. Neurological examination and neuro-electrophysiological studies suggested diabetic lumbosacral radiculo-plexus neuropathy (DLPRN, diabetic amyotrophy). Pain and weakness resolved over time. Case 3: A 58-year-old male was admitted with blurred vision diplopia and complete ptosis of the right eye, with intact pupillary reflexes, shortly after intensification of glucose-lowering treatment with an SGLT2 inhibitor as adjunct to metformin. He was diagnosed with a pupil-sparing third nerve palsy secondary to diabetic mononeuritis which improved over time. While all three acute neuropathies have been previously well described, all are rare and require a high index of clinical suspicion as they are essentially a diagnosis of exclusion. Interestingly, all three of our cases are linked by the development of acute neuropathy following a significant improvement in glycaemic control. This phenomenon is well described in TIN, but not previously highlighted in other acute neuropathies. LEARNING POINTS: A link between acute tightening of glycaemic control and acute neuropathies has not been well described in literature. Clinicians caring for patients with diabetes who develop otherwise unexplained neurologic symptoms following a tightening of glycaemic control should consider the possibility of an acute diabetic neuropathy. Early recognition of these neuropathies can obviate the need for detailed and expensive investigations and allow for early institution of appropriate pain-relieving medications.

Endothelial progenitor cells for the treatment of diabetic vasculopathy: panacea or Pandora's box?

The discovery of endothelial progenitor cell (EPC) a decade ago has refuted the previous belief that vasculogenesis only occurs during embryogenesis. The reduced circulating concentration of EPCs is a surrogate marker of endothelial function and has been implicated in the pathogenesis of many vascular diseases. To date, the therapeutic benefit of neovascularization in ischaemic conditions in a non-diabetic setting has been demonstrated. This article aims to review the biology of EPCs in the diabetic setting with special emphasis on the effects of cardiovascular risk factor modification on EPC phenotype and methods to reverse or augment EPC dysfunction. The potential of the use of EPCs in the treatment of the diabetic vascular dysfunction will also be discussed.

The TBR1-related autistic-spectrum-disorder phenotype and its clinical spectrum.

A diverse range of genetic aberrations can lead to Autistic Spectrum Disorder (ASD) and many of these have been identified via Next Generation Sequencing (NGS) as part of large scale consortium studies. ASD is a phenotypically variable disorder and detailed clinical descriptions are essential to appreciate genotype-phenotype relationships. In this report, we provide a comprehensive clinical description of a child with ASD in whom a TBR1 variant was identified. We review this case in the context of the current TBR1 literature and highlight the variable spectrum of disease associated with this gene. The phenotypic information outlined within the literature is incomplete, exemplifying the limitations of massively-parallel sequencing studies with regards to clinical annotation. We suggest that future reporting of ASD variants should include standardised phenotypic descriptions. This would develop a more thorough understanding of genotype-phenotype relationship, so allowing us to better counsel and support our patients.

All that is hypogonadal in haemochromatosis is not due to iron deposition.

BACKGROUND: Hereditary haemochromatosis (HH) is an autosomal recessive condition resulting in excessive gastrointestinal absorption of iron, which may be deposited in various organs. Apart from diabetes, hypogonadism is the most common endocrinopathy associated with HH and is usually secondary to excess iron deposition in the anterior pituitary gland. AIMS AND METHODS: We present three patients with HH and hypogonadism. RESULTS: Careful clinical and biochemical analysis revealed that the hypogonadism was due to causes other than iron deposition. CONCLUSIONS: This series illustrates the importance of having a high degree of clinical suspicion, even when dealing with what may clinically appear to be a straight-forward clinical problem.

Sibling recurrence of total anomalous pulmonary venous drainage.

Many childhood syndromic disorders are associated with congenital heart defects, but few present specifically with total anomalous pulmonary venous drainage (TAPVD). Here, we report two siblings presenting with TAPVD, tracheo-oesophageal fistula and dysmorphic features in the neonatal period. Careful examination of the mother revealed subtle facial asymmetry and a pre-auricular tag, suggesting a potential variable expression of a dominant disorder. Whole exome sequencing identified a pathogenic heterozygous mutation in EFTUD2, a gene, normally associated with mandibulofacial dystosis Guion-Almedia type (MFDGA), in both siblings and the mother. This is the first report of TAPVD occurring as part of the MFDGA phenotype. It serves to highlight the importance of modern sequencing panels in identifying causative mutations for heterogeneous syndromes such as MFDGA and familial congenital heart defects whilst emphasising the relevance of variable expression when counselling parents.

Hypogonadism in hereditary hemochromatosis.

Hypogonadism, usually hypogonadotropic in origin, is the most common nondiabetic endocrinopathy in hereditary hemochromatosis (HH). Early studies, usually evaluating small numbers of patients with advanced HH, report prevalence rates of 10-100%. The clinical presentation of HH has changed in recent years as a result of increased awareness and screening. We assessed the prevalence of hypogonadism in a large group of patients with HH diagnosed in a single center over the past 20 yr, the period of follow-up spanning the time before and after widespread screening was introduced and the HFE gene was recognized. Abnormally low plasma testosterone levels, with low LH and FSH levels, were found in nine of 141 (6.4%) male patients tested. Eight of nine (89%) had associated hepatic cirrhosis; three of nine (33%) had diabetes. Inappropriately low LH and FSH levels were found in two of 38 females (5.2%) in whom the pituitary-gonadal axis could be assessed. This is the largest detailed study of hypogonadism reported in HH. The lower prevalence of hypogonadism compared with other reported series reflects the earlier diagnosis of HH in an unselected group of patients attending a single center. Patients with lesser degrees of hepatic siderosis at diagnosis are unlikely to develop hypogonadism.

Plasma c-erbB-2 levels in breast cancer patients: prognostic significance in predicting response to chemotherapy.

PURPOSE: To determine the significance of plasma c-erbB-2 levels to assess the extent of disease spread and to predict the response to chemotherapy in node-positive breast cancer patients. METHODS: We determined plasma levels of c-erbB-2 in 79 stages II and III breast cancer patients who received cyclophosphamide, methotrexate, and flourouracil (CMF)/cyclophosphamide, methotrexate, fluorouracil, vincristine, and prednisone (CMFVP) chemotherapy. All patients had a minimum follow-up of greater than 60 months or until disease recurrence. Plasma samples were obtained before and after chemotherapy. Plasma c-erbB-2 levels were quantified by enzyme-linked immunoassay. c-erbB-2 levels were analyzed in relation to the patients' axillary lymph node status, menopausal status, disease status, disease-free survival (DFS), and steroid receptor status of tumor. RESULTS: Plasma c-erbB-2 levels varied widely in breast cancer patients. In general, when all patients were included in the analyses, plasma c-erbB-2 levels before chemotherapy correlated significantly with the number of positive axillary lymph nodes and with postchemotherapy c-erbB-2 levels. No association was observed between pre- or postchemotherapy c-erbB-2 levels and other variables (patients' age at diagnosis, receptor status of the tumor, or disease status). The prognostic significance of different factors (ie, nodal status [one to three v > three positive nodes], menopausal status [pre- v postmenopausal women], estrogen receptor [ER] status [ER+ v ER-], and pre- and postchemotherapy c-erbB-2 levels) in predicting DFS was determined in all study patients. Among the variables examined, nodal status was the strongest predictor of DFS in these patients. The second most significant prognostic marker was postchemotherapy c-erbB-2 level. Prechemotherapy c-erbB-2 levels showed prognostic significance for DFS in a subset of breast cancer patients (ie, patients with > three positive nodes). Patients with greater than three positive lymph nodes and those with greater than 100 fmol/mL of plasma c-erbB-2 levels before therapy had significantly shorter DFS than did those patients with 100 fmol/mL or less c-erbB-2 levels. CONCLUSION: In breast cancer patients, determination of c-erbB-2 levels before therapy is an important biomarker to assess the extent of disease spread in the lymph nodes. Postchemotherapy c-erbB-2 levels are also a prognostic indicator for DFS in patients who receive chemotherapy. Finally, in a subgroup of patients with greater than three positive nodes, prechemotherapy c-erbB-2 levels are a prognostic marker for response of patients to standard chemotherapy.

Celiac disease presenting as resistant hypothyroidism.

The high prevalence of celiac disease in patients with autoimmune hypothyroidism, compared to the general population, has been well documented but screening for celiac disease is not recommended as yet in otherwise asymptomatic hypothyroid patients. In recent years the high prevalence of undiagnosed celiac disease in the general population, largely as a result of the many atypical manifestations of the disease, has become apparent. We report the case of a 58-year-old woman with autoimmune hypothyroidism who was initially suspected of having celiac disease on the basis of apparent resistance to levothyroxine therapy, and who had no other clinical or laboratory clues to suggest the diagnosis. Cases of undiagnosed celiac disease causing levothyroxine malabsorbtion have previously been described, but all previous cases had other obvious manifestations of the disease. We believe that this atypical presentation of celiac disease warrants further attention, and that the diagnosis of celiac disease should always be considered in patients requiring higher than expected doses of thyroid hormone replacement, even in patients with normal bowel habit, and no other apparent manifestations of the disease.

A case of Resistance to Thyroid Hormone without mutation in the thyroid hormone receptor beta.

BACKGROUND: Resistance to Thyroid Hormone (RTH) is a condition caused by tissue hyposensitivity to the effects of circulating thyroid hormone, and may be misdiagnosed as hyperthyroidism. AIMS: We report the first case of RTH in an Irish patient highlighting the clinical features and the pathophysiological mechanism underlying the characteristic laboratory abnormalities found in the condition. METHODS: We describe an isolated case of RTH initially misdiagnosed as hyperthyroidism, and detail the investigations which ultimately led to the correct diagnosis. Genetic screening of the thyroid hormone receptor beta gene was performed. RESULTS: Thyroid function tests including T3 suppression test and TRH-stimulation test suggested a diagnosis of RTH. Genetic testing failed to demonstrate a mutation in the thyroid hormone receptor. CONCLUSION: RTH is a rare inherited condition that may be misdiagnosed as hyperthyroidism. The case we describe most likely results from a de novo mutation in an as yet undiscovered gene. RTH should be considered in patients with elevated thyroid hormone levels and normal TSH so that unnecessary and potentially harmful treatment can be avoided.

Inaccuracies in patient medical histories.

Of patients who completed the same medical history questionnaire twice within a certain time period, 66% had at least 1 significant omission in their history. Consideration is given to the merits of a national medical history computerized database.

Dentures and denture care.

It is unfortunate that some of us are unable to maintain our natural teeth for our entire lives. Loss may occur because of diseases we have, medicines we are taking, or the basic lack of good oral hygiene program. Some patients feel that dentures will make oral care easier, with little or nothing to do since cavities are no longer a threat. Unfortunately, this is not entirely true. Proper cleaning of your dentures and mouth and regularly scheduled visits to your dentist can keep your mouth healthy and the dentures fitting properly for a long time to come.

A silent myocardial infarction in the diabetes outpatient clinic: case report and review of the literature.

UNLABELLED: Silent myocardial ischaemia (SMI), defined as objective evidence of myocardial ischaemia in the absence of symptoms, has important clinical implications for the patient with coronary artery disease. We present a dramatic case of SMI in a diabetes patient who attended annual review clinic with ST elevation myocardial infarction. His troponin was normal on admission but raised to 10.7 ng/ml (normal <0.5) when repeated the next day. His angiogram showed diffused coronary artery disease. We here discuss the implications of silent ischaemia for the patient and for the physician caring for patients with diabetes. LEARNING POINTS: Silent myocardial ischaemia (SMI) is an important clinical entity.SMI is common and occurs with increased frequency in patients with diabetes.SMI is an independent predictor of mortality.Recognition may lead to early intervention.

Barriers to exercise in obese patients with type 2 diabetes.

BACKGROUND: Although regular exercise is a critical component of the management of type 2 diabetes, many patients do not meet their exercise targets. Lack of exercise is associated with obesity and adverse cardiovascular outcomes. AIM: We aimed to assess exercise habits in obese Irish patients with type 2 diabetes to determine if patients are adhering to exercise guidelines and to identify perceived barriers to exercise in this group. DESIGN: A cross-sectional study of obese patients with type 2 diabetes attending routine outpatient diabetes clinics at our institution, a public teaching hospital located on the outskirts of Dublin City. METHODS: A total of 145 obese patients with type 2 diabetes were administered a questionnaire to evaluate exercise habits and perceived barriers to exercise. Anthropometric details were measured. RESULTS: About 47.6% (n = 69) of patients exercised for <150 minutes per week (40% of males, 62% of females; P = 0.019) and these patients had a higher body mass index than those meeting targets (35 vs. 33.5 kg/m(2); P = 0.02). Perceived barriers to exercise were varied, with lack of time and physical discomfort being the most common. Reported barriers to exercise varied with age, gender and marital status. CONCLUSION: This study highlights the challenges facing clinicians in improving exercise levels in patients, and the need to identify the specific barriers to exercise in the individual to improve health outcomes.