Effective replication of human influenza viruses in mice lacking a major alpha2,6 sialyltransferase

The hemagglutinins of influenza viruses isolated from humans typically prefer binding to sialic acid in an alpha2,6 linkage. Presumably, the virus uses the presence of these receptors on the respiratory tract to gain entrance into the host cell. The ST6Gal I sialyltransferase knock-out mouse lacks the main enzyme necessary for the attachment of alpha2,6 sialic acid to N-linked glycoproteins on the cell surface. Yet even in the absence of detectable alpha2,6 sialic acid in the mouse respiratory tract, human influenza viruses can still infect these mice and grow to similar titers in the lung and trachea as compared to wild-type animals. This work demonstrates that the presence of a major alpha2,6 sialic acid on N-linked glycoproteins is not essential for human influenza virus infection in mice.     

Both Langerhans cells and interstitial DC cross-present melanoma antigens and efficiently activate antigen-specific CTL

Dendritic cells (DC) have a unique capacity to present external antigens to CD8(+) T cells, i.e. cross-presentation. However, it is not fully established whether the ability to cross-presentation is restricted to a unique subset of DC in humans. Here, we show that two major myeloid DC subsets, i.e. Langerhans cells (LC) and interstitial DC (Int-DC), have the ability to cross-present antigens to CD8(+) T cells in vitro. LC and Int-DC were obtained from DC generated by culturing human CD34(+)-hematopoietic progenitor cells with GM-CSF, FLT3-L, and TNF-alpha (CD34-DC). Both DC subsets were able to capture necrotic/apoptotic allogeneic melanoma cells and present antigens to CD8(+) T cells, resulting in efficient priming of naive CD8(+) T cells into CTL capable of killing melanoma cells. Strikingly, a single stimulation with either subset (LC or Int-DC) or total CD34-DC loaded with necrotic/apoptotic melanoma cells was sufficient to activate melanoma-specific memory CD8(+) T cells obtained from patients with metastatic melanoma to become effective CTL. Thus, this study provides the rationale to use CD34-DC loaded with necrotic/apoptotic allogeneic melanoma cells in a clinical trial.     

Functionality of a novel follitropin alfa pen injector: results from human factor interactions by patients and nurses

Objective: The main objective of this user experience testing study was to evaluate the impact of human factors on the use of a disposable pen containing follitropin alfa by patients and nurses with special focus on the convenience, safety and ease of use, in different types of stimulation protocols.

Methods: Infertile women trying to conceive, and specialist nurses were recruited across 6 European countries. In total 18 patients and 19 nurses took part in the testing, which included both nurse-patient pairings and in-depth interviews. A standardized list of expected and pre-defined critical steps according to the Instructions for Use (IFU), was used to assess the correct handling of the pen.

Results: During the user experience testing, no critical errors, related to the use of the pen, which could affect the success of the injection process were identified. In general, both nurses and patients found the pen very easy to learn, use and would be confident using the pen for self-injection. Nurses also found the pen very easy to train the patients.

Conclusions: The study provides valuable information on the pen from both patient and nurse perspectives in different simulated scenarios reflecting standard practice.     

Presurgical selection of the ideal aneurysm clip by the use of a three-dimensional planning system

Aneurysm occlusion rate after clipping is higher than after endovascular treatment. However, a certain percentage of incompletely clipped aneurysms remains. Presurgical selection of the proper aneurysm clips could potentially reduce the rate of incomplete clippings caused by inadequate clip geometry. The aim of the present study was to assess whether preoperative 3D image-based simulation allows for preoperative selection of a proper aneurysm clip for complete occlusion in individual cases. Patients harboring ruptured or unruptured cerebral aneurysms prior to surgical clipping were analyzed. CT angiography images were transferred to a 3D surgical-planning station (Dextroscope®) with imported models of 58 aneurysm clips. Intracranial vessels and aneurysms were segmented and the virtual aneurysm clips were placed at the aneurysm neck. Operating surgeons had information about the selected aneurysm clip, and patients underwent clipping. Intraoperative clip selection was documented and aneurysm occlusion rate was assessed by postoperative digital subtraction angiography. Nineteen patients were available for final analysis. In all patients, the most proximal clip at the aneurysm neck was the preselected clip. All aneurysms except one were fully occluded, as assessed by catheter angiography. One aneurysm had a small neck remnant that did not require secondary surgery and was occluded 15 months after surgery. 3D image-based preselection of a proper aneurysm clip can be translated to the operating room and avoids intraoperative clip selection. The associated occlusion rate of aneurysms is high.

     

Pharmacological treatments prescribed to people with autism spectrum disorder (ASD) in primary health care

Rationale

Autism spectrum disorders (ASDs) affect 1 % of children, having significant impact on health and social outcomes. Psychotropic medication use by individuals with ASD in the USA increased over time, and polypharmacy occurred in >50 % of those prescribed. In the UK, no psychotropic drugs are approved in ASDs, and little is known about patterns of pharmacological treatment in the ASD population and associated co-morbidities.

Methods

We used The Health Improvement Network, a nationally representative primary care database, to assess the prevalence of ASD diagnoses, psychotropic drug prescribing and neuropsychiatric co-morbidities of 0–24 year olds between 1992 and 2008.

Results

ASD prevalence increased 65-fold from 0.01 % (1992) to 0.50 % (2008). Psychotropic drugs were prescribed to 29 % (1,619/5,651) of the ASD cohort; the most prescribed drugs were sleep medication (9.7 % of prescribed patients), psychostimulants (7.9 %) and antipsychotics (7.3 %). More patients were given psychostimulants and sleep medications over time from 1.5–6.3 % and 2.2–5.9 % respectively. Thirty-seven per cent of the cohort had ≥1 record of a neuropsychiatric co-morbidity, the most common being developmental difficulties and learning disabilities (12.6 %), behavioural, conduct and personality disorders (11.1 %) and attention deficit hyperactivity disorder (7.5 %).

Conclusions

British physicians are more conservative in prescribing practice than American colleagues. However, use of psychostimulants and antipsychotics is much higher in those with ASD than in the general population. Polypharmacy was seen in 34 % of prescribed patients in 2008. Additional studies examining use, efficacy, and long-term safety of antipsychotics and psychostimulants in autistic individuals are warranted.     

An effect of moderate hepatic impairment on the pharmacokinetics and safety of darapladib

Aim/MethodsThis was a phase 1, open label, non-randomized study designed to assess the pharmacokinetics and safety/tolerability of 10 consecutive once daily 40 mg oral doses of darapladib in subjects with moderate hepatic impairment (n = 12) compared with matched healthy volunteers (n = 12).ResultsFor total darapladib, a small increase in total and peak exposure was observed in the subjects with moderate hepatic impairment compared with the subjects with normal hepatic function. The area under the plasma concentration−time curve during a dosing interval of duration τ (AUC(0,τ), geometric mean 223 ng ml⁻¹ h [90% CI 158, 316 ng ml⁻¹h], in moderate hepatic impaired subjects, vs. geometric mean 186 ng ml⁻¹h [90% CI 159, 217 ng ml⁻¹h], in healthy subjects) and maximum concentration (C_max) were 20% and 7% higher, respectively, in the subjects with moderate hepatic impairment than in the healthy control subjects and there was no change in time to maximum concentration (t_max). Protein binding was performed to measure the amount of unbound drug vs. bound. Steady-state was achieved by day 10 for darapladib and its metabolites (M4, M3 and M10). Darapladib was generally well tolerated, with adverse events (AEs) reported by seven subjects in the hepatic impairment group and three subjects in the healthy matched group (five and one of which were drug-related AEs, respectively). The most common AEs were gastrointestinal. These AEs were mostly mild to moderate and there were no deaths, serious AEs or withdrawals due to AEs.ConclusionsThe results of this phase 1 study show that darapladib (40 mg) is well tolerated and its pharmacokinetics remain relatively unchanged in patients with moderate hepatic impairment.     

Is grandparental childcare socio-economically patterned? Evidence from the English longitudinal study of ageing

Grandparents play a vital role in providing childcare to families. Qualitative research and evidence from parents raise concerns that it is grandparents who are socio-economically disadvantaged who provide grandchild care more regularly, perform more intensive tasks, and care out of financial necessity. However, no European studies have investigated these issues at population level. This study is based on grandparents aged 50+ who looked after grandchildren. Data are from wave 8 of the nationally representative English Longitudinal Study of Ageing (2016/2017). We exploit newly collected information on frequency of grandchild care, activities, and reasons for care. Using multinomial regressions, we first examined the extent to which grandparents’ socio-economic characteristics (wealth and education) are associated with frequency of grandchild care. Second, using logistic regressions, we investigated whether wealth and education are associated with activities and reasons for grandchild care. Overall, grandparents from disadvantaged socio-economic backgrounds were more likely to provide more regular childcare. Similarly, grandparents in the lowest wealth quartile were more involved in hands-on activities (cooking, taking/collecting grandchildren to/from school), whereas highly educated grandparents were more likely to help grandchildren with homework. Finally, better-off grandparents were more likely to look after grandchildren to help parents and provide emotional support and less likely to report difficulty in refusing to provide care. Our findings show that grandparental childcare varies by socio-economic status with more intensive childcare activities falling disproportionately on those with fewer resources, and this may act to exacerbate existing socio-economic inequalities in later life.

     

Clinical investigation of human alpha interferon in chronic myelogenous leukemia

Fifty-one patients with previously untreated or minimally treated chronic myelogenous leukemia in chronic phase received human alpha interferon 3 to 9 X 10(6) units intramuscularly (IM) daily until complete hematologic remission, then at doses ranging from 3 X 10(6) units every other day to 9 X 10(6) units daily. Forty-one (80%) patients achieved a hematologic response, 36 (71%) of them attaining a complete hematologic remission with normal peripheral WBC and differential counts. Responding patients showed continuous but slow normalization of several other blood and marrow parameters including platelet counts, serum lactic dehydrogenase and B12 levels, and marrow cellularity and maturation index. Suppression of the Philadelphia chromosome on serial cytogenetic studies of marrow metaphases was documented in 20 of the 36 patients who achieved complete hematologic remission (56%; 39% of total group), eight of whom (22%) had a decrease of the Philadelphia chromosome-positive metaphases to less than 35%. These changes were persistent for 6 months or longer in 18 patients, seven of whom had continuous suppression of the Philadelphia chromosome to less than 90% for a median of 30+ months (range 21+ to 39+ months). After a median follow-up period of 37 months, 25 patients remain in continued disease control with interferon therapy. The projected 3-year survival rate is 76%, with a yearly death rate of 6%, 9%, and 9% in the first 3 years. Response, Philadelphia chromosome suppression, and survival were significantly better among patients in the low-risk category compared to intermediate- and high-risk categories, as defined by a multivariate analysis-derived prognostic model. The projected 3- year survival rate was 94% for patients who achieved a complete hematologic remission on interferon therapy and 45% for those who did not. Thirteen patients have developed blastic crisis, six with lymphoid and three with undifferentiated morphology. We conclude that human leukocyte alpha interferon effectively controls chronic myeloid leukemia and allows reappearance of diploid hemopoietic cells in some patients.