Tracking autophagy during proliferation and differentiation of trypanosoma brucei

Autophagy is a lysosome-dependent degradation mechanism that sequesters target cargo into autophagosomal vesicles. The Trypanosoma brucei genome contains apparent orthologues of several autophagy-related proteins including an ATG8 family. These ubiquitin-like proteins are required for autophagosome membrane formation, but our studies show that ATG8.3 is atypical. To investigate the function of other ATG proteins, RNAi compatible T. brucei were modified to function as autophagy reporter lines by expressing only either YFP-ATG8.1 or YFP-ATG8.2. In the insect procyclic lifecycle stage, independent RNAi down-regulation of ATG3 or ATG7 generated autophagy-defective mutants and confirmed a pro-survival role for autophagy in the procyclic form nutrient starvation response. Similarly, RNAi depletion of ATG5 or ATG7 in the bloodstream form disrupted autophagy, but did not impede proliferation. Further characterisation showed bloodstream form autophagy mutants retain the capacity to undergo the complex cellular remodelling that occurs during differentiation to the procyclic form and are equally susceptible to dihydroxyacetone-induced cell death as wild type parasites, not supporting a role for autophagy in this cell death mechanism. The RNAi reporter system developed, which also identified TOR1 as a negative regulator controlling YFP-ATG8.2 but not YFP-ATG8.1 autophagosome formation, will enable further targeted analysis of the mechanisms and function of autophagy in the medically relevant bloodstream form of T. brucei

On the Persistence of Mental Health Deterioration during the COVID-19 Pandemic by Sex and Ethnicity in the UK: Evidence from Understanding Society

This is the final version. Available on open access from De Gruyter via the DOI in this recordData and code availability: The research data are distributed by the UK Data Service. Researchers who would like to use Understanding Society need to register with the UK Data Service before being allowed to apply for or download datasets. More information: https://www.understandingsociety.ac.uk/documentation/access-data. The code to replicate the analysis in this letter is publicly available from the Harvard Dataverse repository: https://doi.org/10.7910/DVN/YUOWJEWe use longitudinal data from a representative sample of the UK and compare self-reported mental health, as measured by the GHQ-12 score, at three timepoints (2017–2019, April 2020 and March 2021), for the whole sample and by sex and ethnicity. Out of the 14,382 individuals interviewed in 2017–2019 and April 2020, 10,445 were interviewed again in March 2021. The mean GHQ-12 in April 2020 is 12.37 [95% CI: 12.22, 12.52] and in March 2021 is 12.36 [95% CI: 12.21, 12.51], above that of 2017–2019: 11.13 [95% CI: 10.99, 11.26]. We do not find evidence that the level of mental health goes back to pre-pandemic levels. In terms of inequalities, while the gender gap (mean difference between women and men) in mental health deterioration among White British is closing, there is no clear evidence that the ethnic gap (mean difference between ethnic minorities and White British) among men is changing

Potential excess spend in primary care due to NHS drug tariff variability in vitamin D preparations

Objectives Vitamin D is commonly prescribed in primary care for the prevention and treatment of deficiency and for maintenance after treatment (although supplementation for maintenance and prevention can be bought over-the-counter). There is wide variation in the costs to the NHS in England of oral preparations of vitamin D, even for a single-specific dose and route.1 It is possible that the availability of multiple options for the same intended medicine, the costs of which are unlikely to be known by the prescriber, could result in an inadvertent excess spend. We aimed to estimate the annual cost-saving if only the cheapest vitamin D preparations were prescribed. Design Primary care prescribing data for 2018 were downloaded from NHS Digital (https://digital.nhs.uk).2 Monthly datasets include the number of items, quantity and cost of each drug prescribed and dispensed. Private prescriptions are not recorded. All prescription items relating to the vitamin D preparations colecalciferol and ergocalciferol, regardless of dose, route or manufacturer, were extracted. Data for each specific preparation were aggregated across all practices and all months to give the annual number of items and their cost across England. All liquid and injectable preparations were assumed to be appropriately prescribed and therefore excluded from the analysis. Combined preparations – such as calcium/vitamin D, calcium/alendronate and multivitamins – were also excluded. For each defined dose range of vitamin D, the lowest cost preparation was identified, and the potential cost-savings if only these preparations were prescribed was calculated. Setting Primary care in England. Participants All patients registered with a general practitioner in England in 2018. Main Outcome Measure The difference between actual and potential spend on vitamin D prescriptions, if only the lowest priced preparation were available. Results In 2018, over 4 million vitamin D items were prescribed in primary care, at a cost of over £21 million. If only the cheapest options were prescribed for non-liquid preparations across all dose ranges, and assuming all prescriptions were appropriate, it would have resulted in an approximate £15 million (>70%) cost-saving to the NHS. Maintenance doses of vitamin D (designated as 800 to 2000 international units per day as per NICE guidelines3) accounted for more than half of the spend (∼£12 million). It was noted that all the cheapest options available are suitable for vegetarians. Conclusion The prescribing of more expensive vitamin D preparations in primary care may have significant financial consequences, although our results relate to a single year of prescribing within NHS primary care. Since choice of preparation may intentionally be based on factors other than cost (e.g. dietary requirements, bioavailability, what was initially prescribed by a hospital), work is needed nationally to rationalise available prescribing options. If national guidance were produced, the difficulties of implementation within individual Clinical Commissioning Groups might limit economic benefit. National efficient procurement strategies are an alternative approach, but require careful consideration of legislative frameworks (such as the Public Contract Regulations 20154) with safeguards to prevent horizontal cooperation between suppliers

State of the Art and New Trends from the 2022 Gism Annual Meeting

The 2022 Italian Mesenchymal Stem Cell Group (Gruppo Italiano Staminali Mesenchimali, GISM) Annual Meeting took place on 20–21 October 2022 in Turin (Italy), with the support of the University of Turin and the City of Health and Science of Turin. The novelty of this year’s meeting was its articulation, reflecting the new structure of GISM based on six sections: (1) Bringing advanced therapies to the clinic: trends and strategies, (2) GISM Next Generation, (3) New technologies for 3D culture systems, (4) Therapeutic applications of MSC-EVs in veterinary and human medicine, (5) Advancing MSC therapies in veterinary medicine: present challenges and future perspectives, (6) MSCs: a double-edged sword: friend or foe in oncology. National and international speakers presented their scientific works with the aim of promoting an interactive discussion and training for all attendees. The atmosphere was interactive, where ideas and questions between younger researchers and senior mentors were shared in all moments of the congress

Guidance impact on primary care prescribing rates of simple analgesia: an interrupted time series analysis in England

Background: In March 2018, NHS England published guidance for Clinical Commissioning Groups (CCGs; NHS bodies that commission health services for local areas) to encourage implementation of policy to reduce primary care prescriptions of over-the-counter medications, including simple analgesia. Aims: To investigate: the impact of guidance publication on prescribing rates of simple analgesia (oral paracetamol, oral ibuprofen and topical non-steroidal anti-inflammatory drugs [NSAIDS]) in primary care; CCG implementation intentions; and whether it has created a health inequality based on socioeconomic status. Design and Setting: Interrupted time series analysis of primary care prescribing data in England. Methods: Practice-level prescribing data from January 2015 to March 2019 were obtained from NHS Digital. Interrupted time series analyses assessed the association of guidance publication with prescribing rates. The association between practice-level prescribing rates and Index of Multiple Deprivation score (a marker of socioeconomic deprivation) before and after publication was quantified using multivariable Poisson regression. Freedom of information requests were submitted to all CCGs. Results: There was a 4% reduction in prescribing of simple analgesia following guidance publication (adjusted incidence rate ratio [aIRR] 0.96, 95% CI 0.92-0.99, p=0.027), adjusting for underlying time trend and seasonality. Practice-level prescribing rates were greater in more deprived areas. There was considerable diversity across CCGs in whether or how they chose to implement the guidance. Conclusion: Guidance publication was associated with a small reduction in the prescribing rates of simple analgesia across England, without evidence of creating an additional health inequality. Careful implementation by CCGs would be required to optimise cost-saving to the NHS

Difficulties in Evaluating Lyapunov Exponents for Lie Governed Dynamics

We consider here an environment in which the fact that a semiquantum Hamiltonian obeys SU(2) symmetries poses serious difficulties if one wants to compute Lyapunov exponents.Instituto de Física La Plat

Unusual skin toxicity associated with sustained disease response induced by nivolumab in a patient with non-small cell lung cancer

Introduction: Immunotherapy has shown efficacy in the treatment of different malignancies. Nivolumab, an immune checkpoint inhibitor directed against programmed death-1, has been approved for non-small cell lung cancer (NSCLC) in pretreated patients. Although it is generally well-tolerated, immunotherapy may be complicated by a wide range of immune-mediated adverse events. We describe the case of an uncommon skin toxicity arising as alopecia universalis induced by nivolumab in a patient with NSCLC. Case description: A 58-year-old man received nivolumab for metastatic NSCLC after progression to 3 lines of chemotherapy. The treatment was prescribed in June 2016, and induced a rapid and significant disease response. Nivolumab was well-tolerated until May 2017, when partial alopecia at hair and eyelashes appeared. In the next months, alopecia became complete and extended to the whole body surface. The dermatologic picture was compatible with alopecia areata. A topical steroid therapy was attempted, without benefit. The patient refused systemic treatments and is still undergoing nivolumab without new toxicities and with persistent disease response. Conclusions: This case suggests that alopecia areata may be a rare immune-related adverse event of immune checkpoint agents. Its late onset in our patient is uncommon and unexpected, underlining that the risk of nivolumab-induced toxicity is not limited to the beginning of treatment. Despite its rarity, alopecia areata should be considered in the range of adverse events potentially induced by immune checkpoint inhibitors even in the long term. Potential association between toxicity and efficacy of immunotherapy in NSCLC warrants further investigation

Early immunopathological diagnosis of ichthyosis with confetti in two sporadic cases with new mutations in keratin 10.

Ichthyosis with confetti (IC) is a severe non-syndromic ichthyosis due to heterozygous mutations in the KRT10 gene. The disease manifests at birth with erythroderma and scaling and is characterised by the gradual development of numerous confetti-like spots of normal skin. Diagnosis of IC is frequently delayed until adolescence or even adulthood. We report 2 young children who were first diagnosed as having congenital ichthyosiform erythroderma. However, the development of thick, confluent hyperkeratotic plaques together with the histopathological finding of keratinocyte vacuolisation in the suprabasal epidermis evoked IC. Immunofluorescence analysis showed a highly reduced keratin 10 expression within the cytoplasm of suprabasal keratinocytes and its characteristic mislocalisation to the nuclei. The diagnosis was confirmed by the identification of 2 previously unreported mutations in intron 6 and exon 7 of KRT10. Careful clinical examination then showed the presence of the first spots of normal skin in both patients at the age of 2.5 and 5 years, respectively. These cases point to the usefulness of immunofluorescence analysis of keratin 10 expression for an early diagnosis of IC

Peripheral Determinants of Oxygen Utilization in Heart Failure With Preserved Ejection Fraction

The aim of this study was to determine the arteriovenous oxygen content difference (ΔAVO2) in adult subjects with and without heart failure with preserved ejection fraction (HFpEF) during systemic and forearm exercise. Subjects with HFpEF had reduced ΔAVO2. Forearm diffusional conductance for oxygen, a lumped conductance parameter that incorporates all impediments to the movement of oxygen from red blood cells in skeletal muscle capillaries into the mitochondria within myocytes, was estimated. Forearm diffusional conductance for oxygen was not different among adults with HFpEF, those with hypertension, and healthy control subjects; therefore, diffusional conductance cannot explain the reduced forearm ΔAVO2. Instead, adiposity was strongly associated with ΔAVO2, suggesting an active role for adipose tissue in reducing exercise capacity in patients with HFpEF