Risk Factors for Tuberculosis After Highly Active Antiretroviral Therapy Initiation in the United States and Canada: Implications for Tuberculosis Screening

Background. Screening for tuberculosis prior to highly active antiretroviral therapy (HAART) initiation is not routinely performed in low-incidence settings. Identifying factors associated with developing tuberculosis after HAART initiation could focus screening efforts

Sonodynamic therapy complements PD-L1 immune checkpoint inhibition in a murine model of pancreatic cancer

The emergence of immune checkpoint inhibitors (ICI's) in the past decade has proven transformative in the area of immuno-oncology. The PD-1/PD-L1 axis has been particularly well studied and monoclonal antibodies developed to block either the receptor (anti PD-1) or its associated ligand (anti PD-L1) can generate potent anti-tumour immunity in certain tumour models. However, many "immune cold" tumours remain unresponsive to ICI's and strategies to stimulate the adaptive immune system and make these tumours more susceptible to ICI treatment are currently under investigation. Sonodynamic therapy (SDT) is a targeted anti-cancer treatment that uses ultrasound to activate a sensitiser with the resulting generation of reactive oxygen species (ROS) causing direct cell death by apoptosis and necrosis. SDT has also been shown to stimulate the adaptive immune system in a pre-clinical model of colorectal cancer. In this manuscript, we investigate the ability of microbubble mediated SDT to control tumour growth in a bilateral tumour mouse model of pancreatic cancer by treating the target tumour with SDT and observing the effects at the off-target untreated tumour. The results demonstrated a significant 287% decrease in tumour volume when compared to untreated animals 11 days following the initial treatment with SDT, which reduced further to 369% when SDT was combined with anti-PD-L1 ICI treatment. Analysis of residual tumour tissues remaining after treatment revealed increased levels of infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T-lymphocytes (respectively 4.65 and 3.16-fold more) in the off-target tumours of animals where the target tumour was treated with SDT and anti-PD-L1, when compared to untreated tumours. These results suggest that SDT treatment elicits an adaptive immune response that is potentiated by the anti-PD-L1 ICI in this particular model of pancreatic cancer

Sensitive detection of human papillomavirus in cervical, head/neck, and schistosomiasis-associated bladder malignancies

We assayed for the presence of human papilloma virus (HPV) DNA in serum and/or peripheral blood fraction (PBF) of individuals with cervical, head/neck, or bladder cancer due to schistosomiasis. Using mass spectroscopy coupled with competitive PCR, HPV DNA was detected at the individual molecule level by using “MassARRAY” assays. The resultant sensitivity was superior to real-time fluorescent PCR-based assays, while specificity was maintained. Our principal findings were: (i) Virtually all tested cervical cancers and schistosomiasis-associated bladder cancers, and a plurality of head/neck cancers, are associated with HPV DNA in the tumor. (ii) All 27 bladder cancers due to schistosomiasis were associated with the presence of HPV-16 DNA, which can be detected in tumor and serum but not in PBF. In contrast, no serum HPV-16 DNA signal was detected in seven individuals with schistosomiasis-associated bladder cancers after surgical removal of the tumor. (iii) Among the head/neck cancers we studied, anterior tumors were more often associated with HPV DNA in tumor, serum, and/or PBF than posterior tumors. (iv) In cervical cancer, where all tumors contain HPV DNA, viral DNA could be detected often in serum and/or PBF. Further, HPV-16 DNA was detected in serum and/or PBF of most patients with untreated high-grade cervical dysplasia but disappeared if the dysplasia was eliminated. The sensitive, specific, and quantitative MassARRAY technique should make it feasible to monitor cancer occurrence and treatment and recurrence of malignancies and dysplasias associated with HPV DNA

The Mental Health of Children and Young People

Children and young people were not a priority in the early stages of the pandemic. Whilst children and young people were considered to be at ‘low health risk’ but this did not account for the seriousness of mental health issues. Evidence of the psychological impact of Covid-19 on children and young people is fast emerging. A concerning number of studies and systemic reviews suggest the overwhelming negative impact on child and adolescent mental health. The Buttle UKsurvey (June 22 – 15 July 2021) revealed that the Covid-19 pandemic had exacerbated an ‘under the radar’ mental health crisis leaving a generation of children traumatised and unable to benefit from the Government’s educational recovery programmes. ‘We must listen to frontline professionals and prioritise mental health support’: https://buttleuk.org/news/news-list/state-of-child-poverty-2021/ Our report shows that the primary need for ‘Generation Covid’ is not educational attainment, but emotional recovery and the fostering of resilience; supported by a National UK Strategy for Play, encompassing play provision and facilities in all schools and early years settings. There are currently too many children and young people across England being denied vital mental health support in schools or access to mental health services. The pandemic and subsequent lockdowns have impacted children’s mental health in many different ways. This report highlights the increased levels of anxiety,behavioural issues and increased conflicts at home. It asks for immediate measures to ‘level up’ service provision for children and young people with SEND and those with existing mental health conditions whose needs have been forgotten during the pandemic with our most vulnerable children frequently left unsupported. Prioritising the maintenance of grades and statistics since the pandemic cannot and must not be at the expense of child and adolescent mental wellbeing. Here, we urge the Government to support fully-funded early intervention hubs in schools and communities that address the inequalities that contribute to poor mental health. The hubs should provide an easy access self-referral service for children and young people who fall below the CAMHS threshold. We recommend statutory national in-school counselling and play and creative arts therapy services staffed only by those who are professionally accredited and registered through an independent Government-approved agency such as the Professional Standards Authority (PSA) Accredited Register Programme or the Health and Care Professions Council. On World Mental Health Day (10 October 2021) the Children’s Commissioner, Dame Rachel de Souza observed that the numbers of children with a mental health problem had risen from 1 in 9 before Covid to 1 in 6 now. Outcomes from her Big Ask survey showed that 1 in 5 children were unhappy about the state of their mental health with girls and older children in the most deprived areas the worst affected. A 17-year-old girl who had participated said: ‘The lack of help with mental health has been the biggest thing that has stopped me and my friends from achieving what we want.’ Just over half of the children surveyed (52%) considered good mental health to be one of their key aspirations. But the problem is in no way circumscribed by calendar age. The adverse impact on the very youngest children has been profound; to include toddlers and even younger children in lockdown: ‘You just can’t help but have that stress filter down to children. I think they saw more than we would ever like to admit.’ Mother of a 3-year-old and a 6-month-old: https://www.childrenscommissioner.gov.uk/wpcontent/uploads/2021/09/the_big_ask_the_big_answer_09_2021.pdf The pressure on CAMHS (Child and Adolescent Mental Health Services) with inordinate waiting times and a litany of cancelled appointments pre-dates the pandemic but since the onset of Covid-19, the latest NHS data shows a record number of children referred for urgent mental health treatment (2,260 in June 2021 alone), an increase of 90% on 2020 figures. However, the number of financially cheaper remote appointments has also increased and the steady reduction in face-to-face services has come at a high health cost. ‘We owe it to our children and young people to stop defaulting to giving them the cheap alternative to face-to-face treatment and instead offer them the treatment choice they need...It is simply unacceptable that some of the most vulnerable people in our society ...are not being seen in person. This not only fails to help people get better, it puts them at risk.’ Paul Farmer: Chief Executive of Mind: The Government has allocated £79m to boost previous plans to improve children’s mental healthcare provision and wellbeing in health and education settings as well as initiatives intended to address the wider determinants of mental health. However, many professionals consider this sum to be a drop in the ocean. What is required is sustained investment in research and mental health service provision and the reassurance stemming from a joined-up, system-wide approach to mental health services. A holistic approach to child mental health would addresses the key indicators of risk and vulnerability such as the effects of abuse, environmental and socioeconomic factors and the corrosive effects of poverty. This report recommends a fully-funded National Strategy for Mental Health from the point of pre-conception; a strategy to make early intervention and support for parents and new families a matter of priority. The earlier the intervention the less likely a child will experience the life-long devastation of present and continuing severe mental ill health. Here we examine what is needed from Government, professionals and the family in order for all children to enjoy their birth right of a life founded upon strong mental health and the stability of wellbeing. The Covid 19 pandemic has been a horrific conclusion for so many people of all ages and walks of life. Although we cannot turn back time, we can ensure that there is a brighter future for our children and young people – the adult society of tomorrow