What you need to know about migraine in Hughes syndrome patients.

BACKGROUND: Headache, often migrainous, is common in patients with antiphospholipid antibodies, whether or not they meet Sydney criteria for a definite diagnosis of Hughes syndrome. Migraine may be a harbinger of stroke in this patient population and even refractory migraine may be highly responsive to antithrombotic therapy in this clinical context. PURPOSE: To summarize what is known to date about managing this important manifestation of the immune-mediated hypercoagulable Hughes syndrome. RESULTS: We provide a suggested management algorithm for refractory headache in this unique patient population. CONCLUSION: Most neurologists don't see or recognize many aPL-positive patients in their practice, so hematologists and rheumatologists who see these patients should recognize that refractory headache may be a manifestation of their immune-mediated hypercoagulable disorder and understand that the potential risks of not addressing this issue may be high.

Liver function tests in primary care provide a key opportunity to diagnose and engage patients with hepatitis C.

Since the advent of direct-acting antiviral therapy, the elimination of hepatitis c virus (HCV) as a public health concern is now possible. However, identification of those who remain undiagnosed, and re-engagement of those who are diagnosed but remain untreated, will be essential to achieve this. We examined the extent of HCV infection among individuals undergoing liver function tests (LFT) in primary care. Residual biochemistry samples for 6007 patients, who had venous blood collected in primary care for LFT between July 2016 and January 2017, were tested for HCV antibody. Through data linkage to national and sentinel HCV surveillance databases, we also examined the extent of diagnosed infection, attendance at specialist service and HCV treatment for those found to be HCV positive. Overall HCV antibody prevalence was 4.0% and highest for males (5.0%), those aged 37-50 years (6.2%), and with an ALT result of 70 or greater (7.1%). Of those testing positive, 68.9% had been diagnosed with HCV in the past, 84.9% before the study period. Most (92.5%) of those diagnosed with chronic infection had attended specialist liver services and while 67.7% had ever been treated only 38% had successfully cleared infection. More than half of HCV-positive people required assessment, and potentially treatment, for their HCV infection but were not engaged with services during the study period. LFT in primary care are a key opportunity to diagnose, re-diagnose and re-engage patients with HCV infection and highlight the importance of GPs in efforts to eliminate HCV as a public health concern.

Cardiovascular Risk Management in Type 1 Diabetes.

PURPOSE OF REVIEW: Type 1 diabetes mellitus (T1DM) is associated with increased mortality, with premature cardiovascular disease (CVD) a major factor. To date, research has identified multiple risk factors for this excess CVD liability. However, gaps remain in our understanding of the underlying mechanisms. RECENT FINDINGS: T1DM is generally diagnosed at a young age. Since cardiovascular complications often only manifest at a later stage of life, there is generally less focus in earlier years on reducing CVD risk for affected individuals. This is an area that requires improvement as risk factors might be managed from earlier age to reduce later development of CVD. In this review, we discuss the evidence for cardiovascular risk factors, risk prediction models, candidate surrogate measurements and CVD risk management.

Identification of proteins associated with development of metastasis from cutaneous squamous cell carcinomas (cSCCs) via proteomic analysis of primary cSCCs.

BACKGROUND: Cutaneous squamous cell carcinoma (cSCC) is one of the most common cancers capable of metastasizing. Proteomic analysis of cSCCs can provide insight into the biological processes responsible for metastasis, as well as future therapeutic targets and prognostic biomarkers. OBJECTIVES: To identify proteins associated with development of metastasis in cSCC. METHODS: A proteomic-based approach was employed on 105 completely excised, primary cSCCs, comprising 52 that had metastasized (P-M) and 53 that had not metastasized at 5 years post-surgery (P-NM). Formalin-fixed, paraffin-embedded cSCCs were microdissected and subjected to proteomic profiling after one-dimensional (1D), and separately two-dimensional (2D), liquid chromatography fractionation. RESULTS: A discovery set of 24 P-Ms and 24 P-NMs showed 144 significantly differentially expressed proteins, including 33 proteins identified via both 1D and 2D separation, between P-Ms and P-NMs. Several differentially expressed proteins were also associated with survival in SCCs of other organs. The findings were verified by multiple reaction monitoring on six peptides from two proteins, annexin A5 (ANXA5) and dolichyl-diphosphooligosaccharide-protein glycosyltransferase noncatalytic subunit (DDOST), in the discovery group and validated on a separate cohort (n = 57). Increased expression of ANXA5 and DDOST was associated with reduced time to metastasis in cSCC and decreased survival in cervical and oropharyngeal cancer. A prediction model using ANXA5 and DDOST had an area under the curve of 0·93 (confidence interval 0·83-1·00), an accuracy of 91·2% and higher sensitivity and specificity than cSCC staging systems currently in clinical use. CONCLUSIONS: This study highlights that increased expression of two proteins, ANXA5 and DDOST, is significantly associated with poorer clinical outcomes in cSCC.

Influences of salinity on the physiology and distribution of the Arctic coralline algae, Lithothamnion glaciale (Corallinales, Rhodophyta).

In Greenland, free-living red coralline algae contribute to and dominate marine habitats along the coastline. Lithothamnion glaciale dominates coralline algae beds in many regions of the Arctic, but never in Godthåbsfjord, Greenland, where Clathromorphum sp. is dominant. To investigate environmental impacts on coralline algae distribution, calcification and primary productivity were measured in situ during summers of 2015 and 2016, and annual patterns of productivity in L. glaciale were monitored in laboratory-based mesocosm experiments where temperature and salinity were manipulated to mimic high glacial melt. The results of field and cold-room measurements indicate that both L. glaciale and Clathromorphum sp. had low calcification and photosynthetic rates during the Greenland summer (2015 and 2016), with maximum of 1.225 ± 0.17 or 0.002 ± 0.023 µmol CaCO3  · g-1  · h-1 and -0.007 ±0.003 or -0.004 ± 0.001 mg O2  · L-1  · h-1 in each species respectively. Mesocosm experiments indicate L. glaciale is a seasonal responder; photosynthetic and calcification rates increase with annual light cycles. Furthermore, metabolic processes in L. glaciale were negatively influenced by low salinity; positive growth rates only occurred in marine treatments where individuals accumulated an average of 1.85 ± 1.73 mg · d-1 of biomass through summer. These results indicate high freshwater input to the Godthåbsfjord region may drive the low abundance of L. glaciale, and could decrease species distribution as climate change increases freshwater input to the Arctic marine system via enhanced ice sheet runoff and glacier calving.

Dosing considerations in the use of the direct oral anticoagulants in the antiphospholipid syndrome.

WHAT IS KNOWN AND OBJECTIVES: At least four prospective trials have been initiated investigating the direct oral anticoagulants in the antiphospholipid syndrome. Preliminary reports have supported their use in patients with a history of venous thrombosis and a target INR of 2-3, but there have also been reports of failure of these agents in the antiphospholipid syndrome. The objective is to present a case report that illustrates there may be important dosing issues when considering the use of these agents in patients with the antiphospholipid syndrome. CASE SUMMARY: A 50-year-old woman with the antiphospholipid syndrome, manifesting clinically with recurrent pyoderma gangrenosum-like leg ulcers, was treated with apixaban, resulting in improved ulcer healing. For insurance purposes, she was switched to rivaroxaban with worsening of the ulcers which again improved when apixaban was resumed. WHAT IS NEW AND CONCLUSION: Despite a similar half-life, pharmacokinetics and pharmacodynamics, the manufacturer-recommended maintenance dosing of apixaban is twice daily and rivaroxaban once daily. We believe this difference in recommended dose accounts for the differential clinical response noted in the present case report and that twice daily dosing and a larger daily dose of these agents may be more efficacious in potent hypercoagulable disorders, such as the antiphospholipid syndrome.

A matched comparison study of hepatitis C treatment outcomes in the prison and community setting, and an analysis of the impact of prison release or transfer during therapy.

Prisoners are a priority group for hepatitis C (HCV) treatment. Although treatment durations will become shorter using directly acting antivirals (DAAs), nearly half of prison sentences in Scotland are too short to allow completion of DAA therapy prior to release. The purpose of this study was to compare treatment outcomes between prison- and community-based patients and to examine the impact of prison release or transfer during therapy. A national database was used to compare treatment outcomes between prison treatment initiates and a matched community sample. Additional data were collected to investigate the impact of release or transfer on treatment outcomes. Treatment-naïve patients infected with genotype 1/2/3/4 and treated between 2009 and 2012 were eligible for inclusion. 291 prison initiates were matched with 1137 community initiates: SVRs were 61% (95% CI 55%-66%) and 63% (95% CI 60%-66%), respectively. Odds of achieving a SVR were not significantly associated with prisoner status (P=.33). SVRs were 74% (95% CI 65%-81%), 59% (95% CI 42%-75%) and 45% (95% CI 29%-62%) among those not released or transferred, transferred during treatment, or released during treatment, respectively. Odds of achieving a SVR were significantly associated with release (P<.01), but not transfer (P=.18). Prison-based HCV treatment achieves similar outcomes to community-based treatment, with those not released or transferred during treatment doing particularly well. Transfer or release during therapy should be avoided whenever possible, using anticipatory planning and medical holds where appropriate.

Simulating backspatter of blood from cranial gunshot wounds using pig models.

Few studies have examined the biomechanical basis for backspatter from cranial gunshot wounds. Backspatter is material which travels against the direction of fire following ejection from a gunshot entrance wound. Our paper focuses on the use of animals for reconstructing this phenomenon. Five live pigs and several slaughtered pigs were shot using either 9 × 19 mm, 115 grain, full metal jacketed ammunition or .22 long rifle, 40 grain, lead, round-nose ammunition. A high-speed camera was used to record the entrance wound formation and backspatter. A small amount of backspattered material was produced with all targets, and blood backspatter was seen in a few cases. However, we conclude that our model provides an understanding of the phenomenon of backspatter and the physical mechanisms associated with it. The various components of the mechanism of backspatter formation are complex and overlap. The principle mechanism observed in pig cranial gunshots was the high-speed impact response of the skin overlying the skull bone. This study has also produced evidence supporting the view that backspatter can result from the splashing of superficial blood if it is already present on the skin. Subcutaneous gas effects have been demonstrated for backspatter from contact shots. There has been no clear evidence of the role of the collapse of a temporary cavity within the brain.

The histopathological mimics of inflammatory bowel disease: a critical appraisal.

The pathological diagnosis of inflammatory bowel disease (IBD) is often difficult because biopsy material may not contain pathognomonic features, making distinction between Crohn's disease, ulcerative colitis and other forms of colitides a truly challenging exercise. The problem is further complicated as several diseases frequently mimic the histological changes seen in IBD. Successful diagnosis is reliant on careful clinicopathological correlation and recognising potential pitfalls. This is best achieved in a multidisciplinary team setting when the full clinical history, endoscopic findings, radiology and relevant serology and microbiology are available. In this review, we present an up-to-date evaluation of the histopathological mimics of IBD.

The efficacy and safety of treating hepatitis C in patients with a diagnosis of schizophrenia.

Treating chronic hepatitis C with pegylated interferon alpha may induce or exacerbate psychiatric illness including depression, mania and aggressive behaviour. There is limited data regarding treatment in the context of chronic schizophrenia. We sought to establish the safety and efficacy of treating patients with schizophrenia. Patient and treatment data, prospectively collected on the Scottish hepatitis C database, were analysed according to the presence or absence of a diagnosis of schizophrenia. Time from referral to treatment, and the proportion of patients commencing treatment in each group, was calculated. Outcomes including sustained viral response rates, reasons for treatment termination and adverse events were compared. Of 5497 patients, 64 (1.2%) had a diagnosis of schizophrenia. Patients with schizophrenia (PWS) were as likely to receive treatment as those without [28/61(46%) vs 1639/4415 (37%) P = 0.19]. Sustained viral response (SVR) rates were higher in PWS [21/25 (84%) vs 788/1453 (54%) P < 0.01]. SVR rates by genotype were similar [4/8 (50%) vs 239/684 (35%) Genotype 1 (P = 0.56), 17/17 (100%) vs 599/742 (81%) non-Genotype 1 (P = 0.09)]. Adverse events leading to cessation of treatment were comparable [2/25(8%) vs 189/1453 (13%) P: 0.66]. Patients with schizophrenia are good candidates for hepatitis C treatment, with equivalent SVR and treatment discontinuation rates to patients without schizophrenia.

Postural tachycardia syndrome (POTS) and other autonomic disorders in antiphospholipid (Hughes) syndrome (APS).

BACKGROUND: Antiphospholipid syndrome (APS) is an autoimmune hypercoagulable disorder that has been shown to cause a large number of cardiac and neurological manifestations. Two recent studies have demonstrated abnormalities in cardiovascular autonomic function testing in APS patients without other cardiovascular or autoimmune disease. However, an association between autonomic disorders such as postural tachycardia syndrome and APS has not previously been described. METHODS AND RESULTS: Data were obtained by retrospective chart review. We identified 15 patients who have been diagnosed with APS and an autonomic disorder. The median age of the patients at the time of data analysis was 39 years. The autonomic disorders seen in these patients included postural tachycardia syndrome, neurocardiogenic syncope and orthostatic hypotension. The majority of patients (14/15) were female and the majority (14/15) had non-thrombotic neurological manifestations of APS, most commonly migraine, memory loss and balance disorder. Many also had livedo reticularis (11/15) and Raynaud's phenomenon (nine of 15). In some patients, the autonomic manifestations improved with anticoagulation and/or anti-platelet therapy; in others they did not. Two patients with postural tachycardia syndrome who failed to improve with the usual treatment of APS have been treated with intravenous immunoglobulin with significant improvement in their autonomic symptoms. CONCLUSION: We believe that autonomic disorders in APS may represent an important clinical association with significant implications for treatment.

Synthesis of stable isotope labelled internal standards for drug-drug interaction (DDI) studies.

The syntheses of stable isotope labelled internal standards of important CYP-isoform selective probes, like testosterone 1, diclofenac 3, midazolam 5, and dextromethorphan 7, as well as their corresponding hydroxylated metabolites 6ß-hydroxytestosterone 2, 4'-hydroxydiclofenac 4, 1'-hydroxymidazolam 6 and dextrorphan 8 are reported. Microwave-enhanced H/D-exchange reactions applying either acid, base, or homogeneous and heterogeneous transition metal catalysis, or combinations thereof proved to be highly efficient for direct deuterium labelling of the above mentioned probes. Compared to conventional stepwise synthetic approaches, the combination of H/D exchange and biotransformation provides the potential for considerable time- and cost savings, in particular for the synthesis of the stable isotope labelled internal standards of 4'-hydroxydiclofenac 4 and 1'-hydroxymidazolam 6.

Transdermal buprenorphine plus oral paracetamol vs an oral codeine-paracetamol combination for osteoarthritis of hip and/or knee: a randomised trial.

OBJECTIVE: Low-dose transdermal opioids offer a new therapeutic option for osteoarthritis (OA). This study compared symptom relief obtained with buprenorphine patches plus oral paracetamol with that obtained with an oral codeine-paracetamol combination tablet (co-codamol) in older adults with OA. METHOD: Two hundred and twenty people (aged ≥60 years) with OA hip and/or knee pain were randomised to treatment with 7-day buprenorphine patches plus oral paracetamol (5-25 µg/h buprenorphine patches plus 1000 mg oral paracetamol q.i.d. (4 times daily); n=110) or co-codamol tablets (two 8/500-two 30/500 mg tablets q.i.d.; n=110). They entered a titration period of up to 10 weeks, during which their dose of study medication was adjusted until they reached optimum pain control. Patients who achieved optimum pain control entered a 12-week assessment period. The primary outcome was average daily pain scores recorded using the box scale-11 (BS-11) pain scale. RESULTS: Both treatments significantly reduced patient pain scores. The estimated treatment difference [95% confidence interval (CI)] was -0.02 (-0.64, 0.60) for the per protocol (PP) population. The results were similar for the full analysis population. Patients receiving 7-day buprenorphine patches plus oral paracetamol needed significantly less escape medication (ibuprofen) than those receiving co-codamol tablets (P=0.002; PP population). Less than 10% of patients in the 7-day buprenorphine patches plus oral paracetamol group were receiving the highest dose level at the end of the study, compared with 34% in the co-codamol group. Withdrawal rates were high in both groups. The incidence of adverse events (AEs) was comparable between the groups (86.4% of patients in the 7-day buprenorphine patches plus oral paracetamol group; 81.7% in the co-codamol group). Six serious AEs were reported in three patients (2.7%) in the 7-day buprenorphine patches plus oral paracetamol group and one (0.9%) in the co-codamol group. CONCLUSIONS: 7-day buprenorphine patches plus oral paracetamol were non-inferior to co-codamol tablets with respect to analgesic efficacy in older adults with OA pain in the hip/knee.

Skin conditions are the commonest new reason people present to general practitioners in England and Wales.

BACKGROUND: Knowledge of the prevalence and incidence of skin conditions is a prerequisite for designing clinical services and providing appropriate training for primary health care professionals. In the U.K. the general practitioner and practice nurse are the first point of medical contact for persons with skin conditions. OBJECTIVES: We aimed to obtain contemporary data in age-, gender- and diagnosis-specific detail on persons presenting to primary care with skin problems. Comparisons were made with similar data for other major disease groups and with similar data from other recent years. METHODS: We used surveillance data collected in the Weekly Returns Service (WRS) of the Royal College of General Practitioners during 2006 and trend data for subsequent years. The WRS sentinel practices monitor all consultations by clinical diagnosis in a representative population of 950,000 in England and Wales. RESULTS: For conditions included in chapter XII of the International Classification of Diseases Ninth Revision (ICD9), 15% of the population consulted; a further 9% presented with skin problems classified elsewhere in the ICD9, making a total of 24%. There was no evidence of increasing or decreasing trend since 2006. Skin infections were the commonest diagnostic group, while 20% of children < 12 months were diagnosed with atopic eczema. Considered collectively, the incidence of new episodes of skin disorders (including diagnoses outside chapter XII) exceeded incidences for all other major disease groupings. CONCLUSIONS: Compared with other major disease groups, skin conditions are the most frequent reason for consultation in general practice. This result emphasizes the need for appropriate education and training for all medical students and particularly for continuing education in dermatology for all primary health care professionals.

Tumour angiogenesis: the gap between theory and experiments.

A common experimental technique for viewing in vivo angiogenesis utilises tumours implanted into a test animal cornea. The cornea is avascular but the tumour promotes vascularisation from the limbus and the new blood vessels can be readily observed through the transparent cornea. Many of the early mathematical models for tumour angiogenesis used this scenario as their experimental template and as such assumed that there is a large gap, of the order of 2mm, between the tumour and neighbouring vasculature at the onset of angiogenesis. In this work we consider whether the assumption that there is a significant gap between the tumour and neighbouring vasculature is unique to intra-cornea tumour implants, or whether this characterises avascular tumour growth more generally. To do this we utilise a simple scaling argument, derive a multi-compartment model for tumour growth, and consider in vivo images. This analysis demonstrates that the corneal implant experiments and the corresponding mathematical models cannot generally be applied to a clinical setting.

Assessment of Mars Exploration Rover landing site predictions.

Comprehensive analyses of remote sensing data during the three-year effort to select the Mars Exploration Rover landing sites at Gusev crater and at Meridiani Planum correctly predicted the atmospheric density profile during entry and descent and the safe and trafficable surfaces explored by the two rovers. The Gusev crater site was correctly predicted to be a low-relief surface that was less rocky than the Viking landing sites but comparably dusty. A dark, low-albedo, flat plain composed of basaltic sand and haematite with very few rocks was expected and found at Meridiani Planum. These results argue that future efforts to select safe landing sites based on existing and acquired remote sensing data will be successful. In contrast, geological interpretations of the sites based on remote sensing data were less certain and less successful, which emphasizes the inherent ambiguities in understanding surface geology from remotely sensed data and the uncertainty in predicting exactly what materials will be available for study at a landing site.

Palynological evidence for pre-agricultural reindeer grazing and the later settlement history of the Lycksele region, northern Sweden.

Analyses of high-resolution pollen data, coprophilous fungal spores, microscopic charcoal and sedimentology, combined with radiocarbon dating, allow the assessment of the impact of Sami and Nordic land use in the region surrounding the winter market town of Lycksele in northern Sweden. Such winter markets were established by the Crown during the seventeenth century AD to control the semi-nomadic movements of the Sami who traded here with Finnish settlers and were also taxed and educated. Little is known about Sami and Nordic co-existence beyond these market places, mainly due to a lack of archaeological evidence relating to Sami activity. Vegetation and land-use changes in the region between ~ AD 250 and 1825 reveal no signal for pre-seventeenth century agricultural activity, but the coprophilous fungal spore records suggest the increased regional presence of grazing herbivores (possibly reindeer) between ~ AD 800 and 1100. Sami activity in the parish of Lycksele has been suggested by rich metal finds dated to ~ AD 1000-1350 and they may have been attracted by an abundance of reindeer.

Trends in HbA1c and other biochemical outcomes of individuals with newly diagnosed type 1 diabetes.

BACKGROUND: There is limited data on glycaemic control and cardiovascular risk factor management in newly diagnosed individuals with type 1 diabetes in the first 2 years. METHODS: Retrospective, single centre study from the North West of England, newly diagnosed with type 1 diabetes between 2014 and 2018 (n = 58). HbA1c, blood pressure, lipids and body mass index (BMI) data were collected from electronic patient records from the time of diagnosis until the end of 2 years, stratified by age 16-24 years or ≥ 25 years at presentation. RESULTS: For those aged 16-24 years (n = 31), median (IQR), HbA1c improved at 6 months from 83 (63-93) to 51.5 (46-75) mmol/mol (p = 0.001) and remained stable 6-24 months. For those ≥ 25 years (n = 27), HbA1c declined from 91 (70-107) to 65 (50-89) mmol/mol, (p < 0.01) at 6 months and declined further to 52 mmol/mol (44-70) at 24 months. At 24 months, 27.8% of all individuals had an HbA1c ≥ 69 mmol/mol. Approximately, a third met LDL (< 2 mmol/L) and total cholesterol (< 4 mmol/L) targets. A total of 58.6% of individuals were overweight/obese (BMI > 25 kg/m2) at 24 months compared to 45.8% at baseline. There were no significant blood pressure changes during the follow-up. CONCLUSIONS: In both age groups, significant improvement of HbA1c occurred within the first 6 months of diagnosis with no statistical difference between the two groups at any of the time points up to 24 months. Despite significant improvements in HbA1c, majority had levels > 53 mmol/mol at 24 months. Alongside the high incidence of obesity and dyslipidaemia, our data support the need for further intensification of therapy from diagnosis of type 1 diabetes.