Explore the vast range of titles available.

In the 38 years since the discovery of HTLV-1, the first human retrovirus (transmitted just like the later-found human retrovirus HIV-1), effective intervention strategies have not been actively publicised. [...]HTLV-1 remains a strong threat to individual and community health, and even more so to global health because of the accelerated rate of human migration in recent times. The same approach needs to be applied to HTLV-1, which is horizontally transmitted through close contact with fresh blood and unprotected sex, as well as vertically through breast feeding.8 Reports have highlighted ongoing sexual transmission of HTLV-1 in central Australia,9 Japan10 and South America.11,12 To date, an astounding 17 different prevention strategies have been used widely to reduce the transmission of other blood-borne and sexually transmittable viruses, such as hepatitis B, hepatitis C, and HIV, but not for HTLV-1. Preventive measures for HTLV-1 infection through blood transfusion and organ transplantation, such as screening of donated blood products, have been implemented only in some, but not many, countries in which HTLV-1 is endemic, such as parts of Africa, broadly through the Caribbean, Iran, and Australia among Indigenous people. [...]the systemic screening of donated organs to exclude the transplantation of positive organs is still a neglected issue worldwide.13 Japan's Nagasaki Prefecture introduced routine HTLV-1 antenatal screening and formula feeding of babies of HTLV-1-positive mothers in 1987, resulting in a remarkable reduction of the prevalence of HTLV-1 infection from 7·2% to 1·0%.14 But, so far, this successful prevention of mother-to-child HTLV-1 transmission has been rolled out nationwide in Japan only.

ObjectivesAntiepileptic and antiarrhythmic drugs inhibit voltage-gated sodium (Na+) channels (VGSCs), and preclinical studies show that these medications reduce tumour growth, invasion and metastasis. We investigated the association between VGSC inhibitor use and survival in patients with breast, bowel and prostate cancer.DesignRetrospective cohort study.SettingIndividual electronic primary healthcare records extracted from the Clinical Practice Research Datalink.ParticipantsRecords for 132 996 patients with a diagnosis of breast, bowel or prostate cancer.Outcome measuresAdjusted Cox proportional hazards regression was used to analyse cancer-specific survival associated with exposure to VGSC inhibitors. Exposure to non-VGSC-inhibiting antiepileptic medication and other non-VGSC blockers were also considered. Drug exposure was treated as a time-varying covariate to account for immortal time bias.ResultsDuring 1 002 225 person-years of follow-up, there were 42 037 cancer-specific deaths. 53 724 (40.4%) patients with cancer had at least one prescription for a VGSC inhibitor of interest. Increased risk of cancer-specific mortality was associated with exposure to this group of drugs (HR 1.59, 95% CI 1.56 to 1.63, p<0.001). This applied to VGSC-inhibiting tricyclic antidepressants (HR 1.61, 95% CI 1.50 to 1.65, p<0.001), local anaesthetics (HR 1.49, 95% CI 1.43 to 1.55, p<0.001) and anticonvulsants (HR 1.40, 95% CI 1.34 to 1.48, p<0.001) and persisted in sensitivity analyses. In contrast, exposure to VGSC-inhibiting class 1c and 1d antiarrhythmics was associated with significantly improved cancer-specific survival (HR 0.75, 95% CI 0.64 to 0.88, p<0.001 and HR 0.54, 95% CI 0.33 to 0.88, p=0.01, respectively).ConclusionsAssociation between VGSC inhibitor use and mortality in patients with cancer varies according to indication. Exposure to VGSC-inhibiting antiarrhythmics, but not anticonvulsants, supports findings from preclinical data, with improved survival. However, additional confounding factors may underlie these associations, highlighting the need for further study.

For Pathogens MDPI, it was the year where a special edition on Human T-cell Leukemia Virus Type 1 (HTLV-1) took centre stage, and for people living with HTLV-1 (PLHTLV), it was the year that the World Health Organisation adopted HTLV-1 as a health topic. Pathogen’s Special Issue on HTLV-1 Disease aims to collate recent advances in basic science, clinical and epidemiological research enhancing our understanding of this virus’s pathogenicity. In asymptomatic HTLV-1 carriers, HIV/HCV co-infection and advanced immunodeficiency are significant risk factors for death.

In the absence of clinical data on Human T leukaemia Type 1 and COVID-19 infection, we are providing guidance to clinicians who look after people living with HTLV-1.In the absence of clinical data on Human T leukaemia Type 1 and COVID-19 infection, we are providing guidance to clinicians who look after people living with HTLV-1.

In this study, we report the lowest energy structure of bare Cu13 nanoclusters as a pair of enantiomers at room temperature. Moreover, we compute the enantiomerization energy for the interconversion from minus to plus structures in the chiral putative global minimum for temperatures ranging from 20 to 1300 K. Additionally, employing nanothermodynamics, we compute the probabilities of occurrence for each particular isomer as a function of temperature. To achieve that, we explore the free energy surface of the Cu13 cluster, employing a genetic algorithm coupled with density functional theory. Moreover, we discuss the energetic ordering of isomers computed with various density functionals. Based on the computed thermal population, our results show that the chiral putative global minimum strongly dominates at room temperature.

Corticosteroids are most commonly used to treat HTLV-1-associated myelopathy (HAM); however, their clinical efficacy has not been tested in randomized clinical trials. This randomized controlled trial included 8 and 30 HAM patients with rapidly and slowly progressing walking disabilities, respectively. Rapid progressors were assigned (1:1) to receive or not receive a 3-day course of intravenous methylprednisolone in addition to oral prednisolone therapy. Meanwhile, slow progressors were assigned (1:1) to receive oral prednisolone or placebo. The primary outcomes were a composite of ≥1-grade improvement in the Osame Motor Disability Score or ≥30% improvement in the 10 m walking time (10 mWT) at week 2 for rapid progressors and changes from baseline in 10 mWT at week 24 for slow progressors. In the rapid progressor trial, all four patients with but only one of four without intravenous methylprednisolone achieved the primary outcome (p = 0.14). In the slow progressor trial, the median changes in 10 mWT were −13.8% (95% CI: −20.1–−7.1; p < 0.001) and −6.0% (95% CI: −12.8–1.3; p = 0.10) with prednisolone and placebo, respectively (p for between-group difference = 0.12). Whereas statistical significance was not reached for the primary endpoints, the overall data indicated the benefit of corticosteroid therapy. (Registration number: UMIN000023798, UMIN000024085)

Background/Objectives: Breast cancer is a heterogeneous and complex disease with significant individual differences in molecular immunophenotype, biological behavior, histopathological morphology, and response to chemotherapy. The presence of tumor-infiltrating lymphocytes (TILs) has gained considerable attention due to growing evidence of their involvement in therapeutic efficacy, particularly in the response to neoadjuvant chemotherapy (NACT). Different immune cell subsets’ frequency, location, and functional orientation vary substantially between tumor types and individuals with apparently identical cancers. Currently, next-generation sequencing (NGS) has provided key insights into the composition of the tumor microenvironment. Simultaneously, immunohistochemistry (IHC) of paraffin-embedded biopsies allows the visualization of marker proteins within the immune infiltrate, thereby enhancing our understanding of the role of immune cells in cancer therapy. Methods: This exploratory study evaluated immune cell tumor infiltration using NGS with immune cell deconvolution, as well as automated IHC on Tru-Cut biopsies from 57 patients with locally advanced breast cancer. Image analysis was performed using Qupath v0.6.0 software. The percentage of infiltrating CD4+ or CD8+ T cells was determined, along with the expression of the markers FoxP3, LAG3, CTLA4, PD1, and TIM-3. We aimed to gain insights into the tumor microenvironment and its influence on the response to NACT in patients with breast cancer. Results: Transcriptomic immune deconvolution approaches suggested that a biased cytotoxic tumor environment is linked to chemosensitivity. IHC assays of individual markers reveal that baseline immune cell abundance and individual checkpoint expression did not differ significantly across the response groups. However, the functional organization and coordination of the tumor immune microenvironment showed distinct associations with chemosensitivity. Conclusions: Features representing immune balance, such as CD8/CD4 ratio and T cell-contextualized metrics, emerged as candidate predictors of pathological response to NACT, outperforming molecular phenotype alone in this exploratory cohort.

HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP) is an immune mediated myelopathy caused by the human T-lymphotropic virus type 1 (HTLV-1). The efficacy of treatments used for patients with HAM/TSP is uncertain. The aim of this study is to document the efficacy of pulsed methylprednisolone in patients with HAM/TSP. Data from an open cohort of 26 patients with HAM/TSP was retrospectively analysed. 1g IV methylprednisolone was infused on three consecutive days. The outcomes were pain, gait, urinary frequency and nocturia, a range of inflammatory markers and HTLV-1 proviral load. Treatment was well tolerated in all but one patient. Significant improvements in pain were: observed immediately, unrelated to duration of disease and maintained for three months. Improvement in gait was only seen on Day 3 of treatment. Baseline cytokine concentrations did not correlate to baseline pain or gait impairment but a decrease in tumour necrosis factor-alpha (TNF-α) concentration after pulsed methylprednisolone was associated with improvements in both. Until compared with placebo, treatment with pulsed methylprednisolone should be offered to patients with HAM/TSP for the treatment of pain present despite regular analgesia.

IntroductionVoltage-gated sodium channel (VGSC)-inhibiting drugs are commonly used to treat epilepsy and cardiac arrhythmia. VGSCs are also widely expressed in various cancers, including those of the breast, bowel and prostate. A number of VGSC-inhibiting drugs have been shown to inhibit cancer cell proliferation, invasion, tumour growth and metastasis in preclinical models, suggesting that VGSCs may be novel molecular targets for cancer treatment. Surprisingly, we previously found that prior exposure to VGSC-inhibiting drugs may be associated with reduced overall survival in patients with cancer, but we were unable to control for the cause of death or indication for prescription. The purpose of the present study is to interrogate a different database to further investigate the relationship between VGSC-inhibiting drugs and cancer-specific survival.Methods and analysisA cohort study using primary care data from the Clinical Practice Research Datalink database will include patients with diagnosis of breast, bowel and prostate cancer (13 000). The primary outcome will be cancer-specific survival from the date of cancer diagnosis. Cox proportional hazards regression will be used to compare survival of patients taking VGSC-inhibiting drugs (including antiepileptic drugs and class I antiarrhythmic agents) with patients with cancer not taking these drugs, adjusting for cancer type, age and sex. Drug exposure will be treated as a time-varying covariate to account for potential immortal time bias. Various sensitivity and secondary analyses will be performed.Ethics and disseminationThe project has been reviewed and approved by the University of York Ethical Review Process. Results will be presented at an international conference and published in open access peer-reviewed journals according to the STROBE and RECORD guidelines.