Efficacy and tolerability of an endogenous metabolic modulator (AXA1125) in fatigue-predominant long COVID: a single-centre, double-blind, randomised controlled phase 2a pilot study

Background: ‘Long COVID’ describes persistent symptoms, commonly fatigue, lasting beyond 12 weeks following SARS-CoV-2 infection. Potential causes include reduced mitochondrial function and cellular bioenergetics. AXA1125 has previously increased β-oxidation and improved bioenergetics in preclinical models along with certain clinical conditions, and therefore may reduce fatigue associated with Long COVID. We aimed to assess the efficacy, safety and tolerability of AXA1125 in Long COVID. / Methods: Patients with fatigue dominant Long COVID were recruited in this single-centre, double-blind, randomised controlled phase 2a pilot study completed in the UK. Patients were randomly assigned (1:1) using an Interactive Response Technology to receive either AXA1125 or matching placebo in a clinical based setting. Each dose (33.9 g) of AXA1125 or placebo was administered orally in a liquid suspension twice daily for four weeks with a two week follow-up period. The primary endpoint was the mean change from baseline to day 28 in the phosphocreatine (PCr) recovery rate following moderate exercise, assessed by 31P-magnetic resonance spectroscopy (MRS). All patients were included in the intention to treat analysis. This trial was registered at ClinicalTrials.gov, NCT05152849. / Findings: Between December 15th 2021, and May 23th 2022, 60 participants were screened and 41 participants were randomised and included in the final analysis. Changes in skeletal muscle phosphocreatine recovery time constant (τPCr) and 6-min walk test (6MWT) did not significantly differ between treatment (n = 21) and placebo group (n = 20). However, treatment with AXA1125 was associated with significantly reduced day 28 Chalder Fatigue Questionnaire [CFQ-11] fatigue score when compared with placebo (least squares mean difference [LSMD] −4.30, 95% confidence interval (95% CI) −7.14, −1.47; P = 0.0039). Eleven (52.4%, AXA1125) and four (20.0%, placebo) patients reported treatment-emergent adverse events; none were serious, or led to treatment discontinuation. / Interpretation: Although treatment with AXA1125 did not improve the primary endpoint (τPCr-measure of mitochondrial respiration), when compared to placebo, there was a significant improvement in fatigue-based symptoms among patients living with Long COVID following a four week treatment period. Further multicentre studies are needed to validate our findings in a larger cohort of patients with fatigue-dominant Long COVID. / Funding: Axcella Therapeutics

Options for early breast cancer follow-up in primary and secondary care : a systematic review

Background Both incidence of breast cancer and survival have increased in recent years and there is a need to review follow up strategies. This study aims to assess the evidence for benefits of follow-up in different settings for women who have had treatment for early breast cancer. Method A systematic review to identify key criteria for follow up and then address research questions. Key criteria were: 1) Risk of second breast cancer over time - incidence compared to general population. 2) Incidence and method of detection of local recurrence and second ipsi and contra-lateral breast cancer. 3) Level 1–4 evidence of the benefits of hospital or alternative setting follow-up for survival and well-being. Data sources to identify criteria were MEDLINE, EMBASE, AMED, CINAHL, PSYCHINFO, ZETOC, Health Management Information Consortium, Science Direct. For the systematic review to address research questions searches were performed using MEDLINE (2011). Studies included were population studies using cancer registry data for incidence of new cancers, cohort studies with long term follow up for recurrence and detection of new primaries and RCTs not restricted to special populations for trials of alternative follow up and lifestyle interventions. Results Women who have had breast cancer have an increased risk of a second primary breast cancer for at least 20 years compared to the general population. Mammographically detected local recurrences or those detected by women themselves gave better survival than those detected by clinical examination. Follow up in alternative settings to the specialist clinic is acceptable to women but trials are underpowered for survival. Conclusions Long term support, surveillance mammography and fast access to medical treatment at point of need may be better than hospital based surveillance limited to five years but further large, randomised controlled trials are needed

Peripheral Nervous System Function and Organophosphate Pesticide Use among Licensed Pesticide Applicators in the Agricultural Health Study

Background: Evidence is limited that long-term human exposure to organophosphate (OP) pesticides, without poisoning, is associated with adverse peripheral nervous system (PNS) function

Static stretching of the hamstring muscle for injury prevention in football codes: a systematic review

Purpose: Hamstring injuries are common among football players. There is still disagreement regarding prevention. The aim of this review is to determine whether static stretching reduces hamstring injuries in football codes. Methods: A systematic literature search was conducted on the online databases PubMed, PEDro, Cochrane, Web of Science, Bisp and Clinical Trial register. Study results were presented descriptively and the quality of the studies assessed were based on Cochrane’s ‘risk of bias’ tool. Results: The review identified 35 studies, including four analysis studies. These studies show deficiencies in the quality of study designs. Conclusion: The study protocols are varied in terms of the length of intervention and follow-up. No RCT studies are available, however, RCT studies should be conducted in the near future

Design and conduct of Caudwell Xtreme Everest: an observational cohort study of variation in human adaptation to progressive environmental hypoxia

Background: The physiological responses to hypoxaemia and cellular hypoxia are poorly understood, and inter-individual differences in performance at altitude and outcome in critical illness remain unexplained. We propose a model for exploring adaptation to hypoxia in the critically ill: the study of healthy humans, progressively exposed to environmental hypobaric hypoxia (EHH). The aim of this study was to describe the spectrum of adaptive responses in humans exposed to graded EHH and identify factors (physiological and genetic) associated with inter-individual variation in these responses.MethodsDesign: Observational cohort study of progressive incremental exposure to EHH.Setting: University human physiology laboratory in London, UK (75 m) and 7 field laboratories in Nepal at 1300 m, 3500 m, 4250 m, 5300 m, 6400 m, 7950 m and 8400 m.Participants: 198 healthy volunteers and 24 investigators trekking to Everest Base Camp (EBC) (5300 m). A subgroup of 14 investigators studied at altitudes up to 8400 m on Everest.Main outcome measures: Exercise capacity, exercise efficiency and economy, brain and muscle Near Infrared Spectroscopy, plasma biomarkers (including markers of inflammation), allele frequencies of known or suspected hypoxia responsive genes, spirometry, neurocognitive testing, retinal imaging, pupilometry. In nested subgroups: microcirculatory imaging, muscle biopsies with proteomic and transcriptomic tissue analysis, continuous cardiac output measurement, arterial blood gas measurement, trans-cranial Doppler, gastrointestinal tonometry, thromboelastography and ocular saccadometry.Results: Of 198 healthy volunteers leaving Kathmandu, 190 reached EBC (5300 m). All 24 investigators reached EBC. The completion rate for planned testing was more than 99% in the investigator group and more than 95% in the trekkers. Unique measurements were safely performed at extreme altitude, including the highest (altitude) field measurements of exercise capacity, cerebral blood flow velocity and microvascular blood flow at 7950 m and arterial blood gas measurement at 8400 m.Conclusions: This study demonstrates the feasibility and safety of conducting a large healthy volunteer cohort study of human adaptation to hypoxia in this difficult environment. Systematic measurements of a large set of variables were achieved in 222 subjects and at altitudes up to 8400 m. The resulting dataset is a unique resource for the study of genotype: phenotype interactions in relation to hypoxic adaptation

The acceptability of intermittent preventive treatment of malaria in infants (IPTi) delivered through the expanded programme of immunization in southern Tanzania

BACKGROUND\ud \ud Intermittent preventive treatment of malaria in infants (IPTi) reduces the incidence of clinical malaria. However, before making decisions about implementation, it is essential to ensure that IPTi is acceptable, that it does not adversely affect attitudes to immunization or existing health seeking behaviour. This paper reports on the reception of IPTi during the first implementation study of IPTi in southern Tanzania.\ud \ud METHODS\ud \ud Data were collected through in-depth interviews, focus group discussions and participant observation carried out by a central team of social scientists and a network of key informants/interviewers who resided permanently in the study sites.\ud \ud RESULTS\ud \ud IPTi was generally acceptable. This was related to routinization of immunization and resonance with traditional practices. Promoting "health" was considered more important than preventing specific diseases. Many women thought that immunization was obligatory and that health staff might be unwilling to assist in the future if they were non-adherent. Weighing and socialising were important reasons for clinic attendance. Non-adherence was due largely to practical, social and structural factors, many of which could be overcome. Reasons for non-adherence were sometimes interlinked. Health staff and "road to child health" cards were the main source of information on the intervention, rather than the specially designed posters. Women did not generally discuss child health matters outside the clinic, and information about the intervention percolated slowly through the community. Although there were some rumours about sulphadoxine pyrimethamine (SP), it was generally acceptable as a drug for IPTi, although mothers did not like the way tablets were administered. There is no evidence that IPTi had a negative effect on attitudes or adherence to the expanded programme on immunisation (EPI) or treatment seeking or existing malaria prevention.\ud \ud CONCLUSION\ud \ud In order to improve adherence to both EPI and IPTi local priorities should be taken into account. For example, local women are often more interested in weighing than in immunization, and they view vaccination and IPTi as vaguely "healthy" rather preventing specific diseases. There should be more emphasis on these factors and more critical consideration by policy makers of how much local knowledge and understanding is minimally necessary in order to make interventions successful

Osvaldo and Isis retrotransposons as markers of the Drosophila buzzatii colonization in Australia

Background: Transposable elements (TEs) constitute an important source of genetic variability owing to their jumping and regulatory properties, and are considered to drive species evolution. Several factors that are able to induce TE transposition in genomes have been documented (for example environmental stress and inter- and intra-specific crosses) but in many instances the reasons for TE mobilisation have yet to be elucidated. Colonising populations constitute an ideal model for studying TE behaviour and distribution as they are exposed to different environmental and new demographic conditions. In this study, the distribution of two TEs, Osvaldo and Isis, was examined in two colonising populations of D. buzzatii from Australia. Comparing Osvaldo copy numbers between Australian and Old World (reported in previous studies) colonisations provides a valuable tool for elucidating the colonisation process and the effect of new conditions encountered by colonisers on TEs. Results: The chromosomal distributions of Osvaldo and Isis retrotransposons in two colonising populations of D. buzzatii from Australia revealed sites of high insertion frequency (>10%) and low frequency sites. Comparisons between Osvaldo insertion profiles in colonising populations from the Old World and Australia demonstrate a tendency towards a higher number of highly occupied sites with higher insertion frequency in the Old World than in Australian populations. Tests concerning selection against deleterious TE insertions indicate that Isis is more controlled by purifying selection than Osvaldo. The distribution of both elements on chromosomal arms follows a Poisson distribution and there are non-significant positive correlations between highly occupied sites and chromosomal inversions. Conclusions: The occupancy profile of Osvaldo and Isis retrotransposons is characterised by the existence of high and low insertion frequency sites in the populations. These results demonstrate that Australian D. buzzatii populations were subjected to a founder effect during the colonisation process. Moreover, there are more sites with high insertion frequency in the Old World colonisation than in the Australian colonisation, indicating a probable stronger bottleneck effect in Australia. The results suggest that selection does not seem to play a major role, compared to demography, in the distribution of transposable elements in the Australian populations

The low-virulent African swine fever virus (ASFV/NH/P68) induces enhanced expression and production of relevant regulatory cytokines (IFNα, TNFα and IL12p40) on porcine macrophages in comparison to the highly virulent ASFV/L60

The impact of infection by the low-virulent ASFV/NH/P68 (NHV) and the highly virulent ASFV/L60 (L60) isolates on porcine macrophages was assessed through the quantification of IFNα, TNFα, IL12p40, TGFβ and ASFV genes by real-time PCR at 2, 4 and 6 h post-infection. Increased IFNα, TNFα and IL12p40 expression was found in infection with NHV, in which expression of TGFβ was lower than in infection with L60. Principal component analysis showed a positive interaction of cytokines involved in cellular immune mechanisms, namely IFNα and IL12p40 in the NHV infection. Quantification by ELISA confirmed higher production of IFNα, TNFα and IL12p40 in the NHV-infected macrophages. Overall, our studies reinforce and clarify the effect of the NHV infection by targeting cellular and cellular-based immune responses relevant for pig survival against ASFV infection

Description and validation of a Markov model of survival for individuals free of cardiovascular disease that uses Framingham risk factors

BACKGROUND: Estimation of cardiovascular disease risk is increasingly used to inform decisions on interventions, such as the use of antihypertensives and statins, or to communicate the risks of smoking. Crude 10-year cardiovascular disease risk risks may not give a realistic view of the likely impact of an intervention over a lifetime and will underestimate of the risks of smoking. A validated model of survival to act as a decision aid in the consultation may help to address these problems. This study aims to describe the development of such a model for use with people free of cardiovascular disease and evaluates its accuracy against data from a United Kingdom cohort. METHODS: A Markov cycle tree evaluated using cohort simulation was developed utilizing Framingham estimates of cardiovascular risk, 1998 United Kingdom mortality data, the relative risk for smoking related non-cardiovascular disease risk and changes in systolic blood pressure and serum total cholesterol total cholesterol with age. The model's estimates of survival at 20 years for 1391 members of the Whickham survey cohort between the ages of 35 and 65 were compared with the observed survival at 20-year follow-up. RESULTS: The model estimate for survival was 75% and the observed survival was 75.4%. The correlation between estimated and observed survival was 0.933 over 39 subgroups of the cohort stratified by estimated survival, 0.992 for the seven 5-year age bands from 35 to 64, 0.936 for the ten 10 mmHg systolic blood pressure bands between 100 mmHg and 200 mmHg, and 0.693 for the fifteen 0.5 mmol/l total cholesterol bands between 3.0 and 10.0 mmol/l. The model significantly underestimated mortality in those people with a systolic blood pressure greater than or equal to 180 mmHg (p = 0.006). The average gain in life expectancy from the elimination of cardiovascular disease risk as a cause of death was 4.0 years for all the 35 year-old men in the sample (n = 24), and 1.8 years for all the 35 year-old women in the sample (n = 32). CONCLUSIONS: This model accurately estimates 20-year survival in subjects from the Whickham cohort with a systolic blood pressure below 180 mmHg