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Long-term testosterone therapy in type 2 diabetes is associated with reduced mortality without improvement in conventional cardiovascular risk factors.
No full textOBJECTIVES
To further characterize the beneficial impact of testosterone replacement therapy (TRT) on the association between mortality and hypogonadism (HG) in men with type 2 diabetes (T2DM), by determining, firstly, if changes in cardiovascular disease (CVD) risk factors after TRT play a role, secondly, whether the reduction in mortality is lost when TRT is discontinued and, finally, the presence of subgroups where benefit may be greater.
MATERIALS AND METHODS
We studied 857 men with T2DM, screened for the BLAST randomized controlled trial, over 3.8 years of follow-up. The men were stratified first by testosterone levels: group 1: total testosterone (TT) >12 nmol/L and free testosterone (FT) >0.25 nmol/L; Group 2: TT ≤12 nmol/L or FT ≤0.25 nmol/L. Group 2 was further stratified into those not on TRT (Group 2a) and those on TRT (Group 2b). Group 2b was further stratified by whether TRT was discontinued (Group 2b1) or not (Group 2b2). The principal outcome, mortality, was studied using Cox regression.
RESULTS
We found that TRT was not associated with improvements in CVD risk factors. CVD risk factors (baseline and changes during follow-up) were not associated with mortality. Men in Group 1 and Group 2b were found to have lower mortality (reference: Group 2a), even with CVD risk factors included in the regression models. Mortality was lower in men in Group 2b1 (6.2%) and Group 2b2 (0%) compared with those in Group 2a (16.9%). The lower mortality associated with Group 1 and Group 2b was observed primarily in older (>64.6 years) and less overweight (≤93.8 kg) men.
CONCLUSIONS
The benefits associated with normal testosterone levels and TRT (even after discontinuation) do not appear to be related to improvements in the CVD risk factors studied. In view of TRT having greater impact in men of lower weight, better outcomes may be achieved with concurrent TRT and weight reduction programmes
Subclinical Reactivation of Cytomegalovirus Drives CD4+CD28null T-Cell Expansion and Impaired Immune Response to Pneumococcal Vaccination in Antineutrophil Cytoplasmic Antibody-Associated Vasculitis.
No full textBackground
Infection is the leading cause of death in antineutrophil cytoplasmic antibody-associated vasculitis (AAV). Expansion of CD4+CD28null T cells is associated with increased risk of infection and mortality, but is only present in cytomegalovirus (CMV)-seropositive individuals. We hypothesized that subclinical CMV reactivation drives CD4+CD28null T-cell expansion, that this is associated with impaired immune response to heterologous antigens, and that antiviral therapy may ameliorate this.
Methods
In a proof-of-concept open-label clinical trial, 38 CMV-seropositive AAV patients were randomized to receive valacyclovir for 6 months or no intervention. CMV reactivation was measured monthly in plasma and urine. CD4+CD28null T cells were enumerated at baseline and at 6 months. At 6 months, 36 patients were vaccinated with a 13-valent pneumococcal vaccine. Serotype-specific immunoglobulin G was assayed before and 4 weeks postvaccination to calculate the antibody response ratio.
Results
Valacyclovir treatment suppressed subclinical CMV reactivation and reduced CD4+CD28null T-cell proportion. CD4+CD28null T-cell reduction correlated with improved vaccine response, whereas CMV reactivation associated with reduced response to vaccination. Furthermore, expansion of CD4+CD28null T cells was associated with a reduction in the functional capacity of the CD4 compartment.
Conclusions
Suppression of CMV may improve the immune response to a T-cell-dependent pneumococcal vaccination in patients with AAV, thus offering potential clinical benefit.
Clinical Trials Registration
NCT01633476
Ribavirin for Hepatitis E Virus Infection After Organ Transplantation: A Large European Retrospective Multicenter Study.
No full textBACKGROUND
Ribavirin is currently recommended for treating chronic hepatitis E virus (HEV) infection. This retrospective European multicenter study aimed to assess the sustained virological response (SVR) in a large cohort of solid organ transplant (SOT) recipients with chronic HEV infection treated with ribavirin monotherapy (N = 255), to identify the predictive factors for SVR, and to evaluate the impact of HEV RNA mutations on virological response.
METHODS
Data from 255 SOT recipients with chronic HEV infection from 30 European centers were analyzed. Ribavirin was given at the median dose of 600 (range, 29-1200) mg/day (mean, 8.6 ± 3.6 mg/kg/day) for a median duration of 3 (range, 0.25-18) months.
RESULTS
After a first course of ribavirin, the SVR rate was 81.2%. It increased to 89.8% when some patients were offered a second course of ribavirin. An increased lymphocyte count at the initiation of therapy was a predictive factor for SVR, while poor hematological tolerance of ribavirin requiring its dose reduction (28%) and blood transfusion (15.7%) were associated with more relapse after ribavirin cessation. Pretreatment HEV polymerase mutations and de novo mutations under ribavirin did not have a negative impact on HEV clearance. Anemia was the main adverse event.
CONCLUSIONS
This large-scale retrospective study confirms that ribavirin is highly efficient for treating chronic HEV infection in SOT recipients and shows that the predominant HEV RNA polymerase mutations found in this study do not affect the rate of HEV clearance.This large-scale retrospective study that included 255 solid organ transplant recipients confirms that ribavirin is highly efficient for treating chronic hepatitis E virus (HEV) infection and shows that HEV RNA polymerase mutations do not play a role in HEV clearance
The European Association for Clinical Pharmacology and Therapeutics-25 years' young and going strong.
No full textClinical pharmacology as a scientific discipline and medical specialty was unarguably born in the twentieth century. Whilst pharmacology-the science behind the treatment of disease-had been in evolution since at least medieval times, the clinical discipline of pharmacology has had a more recent genesis and rather insidious evolution. During the 1900s, there were some clear father (parent) figures of clinical pharmacology in Europe that emerged and were responsible for the development of the specialty in this continent. This was a time when there were parallel developments in geographically dispersed academic departments (around the globe), during an age of excitement in drug discovery and clinical application of new therapeutic agents. It was the meeting of minds of some of these progenitors of the specialty that led to the development of the European Association for Clinical Pharmacology and Therapeutics (EACPT) 25 years ago arising from a working party supported by the World Health Organization in Europe. The EACPT now includes all major national organizations for clinical pharmacology in Europe, representing over 4000 individual professionals interested in clinical pharmacology and therapeutics. The EACPT has a major interest in promoting the safe use of medicines across Europe and internationally and has supported these aims since 1995, through biennial international scientific congresses and summer schools with delegates and presenters from around the world as well as various working group activities. In this article, the current executive committee members of EACPT recall this history, describe the evolution of the association over the last quarter of a century, and provide an update on the activities and ambitions of the association today
Towards the future: The final issue of the journal of the Royal Army Medical Corps 1903-2019.
No full textRetinal Ganglion Cells Die by Necroptotic Mechanisms in a Site-Specific Manner in a Rat Blunt Ocular Injury Model.
No full textClosed-globe injury can cause visual loss in military and civilian populations, with retinal cell death, including retinal ganglion cell (RGC) degeneration, leading to irreversible blindness. RGC and optic nerve (ON) degeneration after eye or head injury is termed traumatic optic neuropathy (TON). There are currently no treatments for RGC loss, therefore novel therapeutics to prevent RGC death or promote axonal regeneration are a priority. We investigated necroptotic signaling mechanisms in a rat blunt ocular injury model. After bilateral blunt trauma, protein expression and retinal localization of necroptosis pathway members (receptor interacting protein kinase 1, RIPK1; receptor interacting protein kinase 3, RIPK3; and mixed lineage kinase domain like pseudokinase, MLKL) were assessed by Western blot and immunohistochemistry (IHC), and potent necroptosis inhibitor Necrostatin-1s (Nec-1s) was delivered by intravitreal injection to one eye and vehicle to the contralateral eye. RGC and photoreceptor survival were assessed by cell counting and outer nuclear layer (ONL) thickness measurements on histology. The neuroprotective effects of Nec-1s were assessed in primary retinal culture by βIII-tubulin RGC cell counts. MLKL protein expression were upregulated at 48 h after injury and MLKL immunolocalised to retinal binding protein with multiple splice (RBPMS) RGC, inner nuclear cells and ONL cells, specifically at the retinal injury site. RIPK3 expression did not increase but RIPK3 co-immunolocalised with RBPMS RGC in intact and injured retinae. In vitro, a Nec-1s concentration of 0.01 pg/µL was RGC neuroprotective. In the blunt ocular injury rat model, Nec-1s prevented RGC death at the center of the impact site but did not protect against ONL thinning or provide functional restitution. RGC degeneration in our blunt ocular injury model is site-specific, with necroptosis driving death at the center of the focal impact site
Laboratory coagulation tests and emicizumab treatment A United Kingdom Haemophilia Centre Doctors' Organisation guideline.
No full textINTRODUCTION
The factor VIII mimetic emicizumab (Hemlibra, Hoffman-la Roche, Basel, Switzerland) has a novel mode of action that affects the laboratory monitoring of patients receiving this treatment.
AIM
This guideline from the United Kingdom Haemophilia Centre Doctors Organisation (UKHCDO) aims to provide advice for clinical and laboratory staff on appropriate use of laboratory assays in patients with Haemophilia A treated with emicizumab.
METHODOLOGY
The guideline was prepared by a review of the available literature and discussion and revision by the authors.
RESULTS
The guideline describes the effect of emicizumab on commonly used coagulations tests and provides recommendations on the use of assays for measurement of factor VIII and factor VIII inhibitor in the presence of emicizumab. The guideline also provides recommendations on measurement of emicizumab.
CONCLUSION
Knowledge of the effect of emicizumab on coagulation tests and factor assays is required to ensure appropriate testing and monitoring of therapy in patients receiving this drug
(Doctor…My child keeps falling over) unexpected MRI findings in children with history of frequent falls and dizziness: a case series.
No full textFrequent falls and dizziness are common complaints in children. These symptoms can be caused by wide range of underlying pathologies including peripheral vestibular deficits, cardiac disease, central lesions, motor skills delay and psychogenic disorders. We report three paediatric cases who presented with complaints of repeated falls and imbalance. MRI scan revealed underlying brain lesions (frontal lobe arteriovenous malformation, exophytic brain stem glioma and cerebellomedullary angle arachnoid cyst with cerebellar tonsillar ectopia). By reporting these cases, we would like to emphasise the importance of a thorough assessment of children with similar symptoms by detailed clinical history, physical examination and maintaining low threshold for investigations, including radiological imaging. Taking in consideration, the wide range of differential diagnosis, the challenge of obtaining detailed history and difficulty of performing reliable physical examination in this age group. Management of underlying disorders can be medical, surgical or just observational
Temporal trends in survival following ward-based NIV for acute hypercapnic respiratory failure in patients with COPD.
No full textINTRODUCTION
Non-invasive ventilation (NIV) is recommended for treatment of acute hypercapnic respiratory failure (AHRF) in acute exacerbations of COPD. National UK audit data suggests that mortality rates are rising in COPD patients treated with NIV.
OBJECTIVE
To investigate temporal trends in in-hospital mortality in COPD patients undergoing a first episode of ward-based NIV for AHRF.
METHODS
Retrospective study of hospitalised COPD patients treated with a first episode of ward-based NIV at a large UK teaching hospital between 2004 to 2017. Patients were split into two cohorts based on year of admission, 2004-2010 (Cohort 1) and 2013-2017 (Cohort 2), to facilitate comparison of patient characteristics.
RESULTS
In total, 547 unique patients were studied. There was no difference in in-hospital mortality rate between the time periods studied (17.6% vs. 20.5%, p=0.378). In Cohort 2 there were more females, a higher rate of co-morbid bronchiectasis and pneumonia on admission and more severe acidosis, hypercapnia and hypoxia. More patients in Cohort 2 had NIV as the ceiling of treatment. Patients in Cohort 2 experienced a longer time from AHRF diagnosis to application of NIV, higher maximum inspiratory positive airway pressure, lower maximum oxygen and shorter duration of NIV. Finally, patients in Cohort 2 experienced a shorter hospital length of stay (LOS), with no differences observed in rate of transfer to critical care or intubation.
CONCLUSION
In-hospital mortality remained stable and LOS decreased over time, despite greater comorbidity and more severe AHRF in COPD patients treated for the first time with ward-based NIV. This article is protected by copyright. All rights reserved