Short- and long-range cis interactions between integrated HPV genomes and cellular chromatin dysregulate host gene expression in early cervical carcinogenesis.

Development of cervical cancer is directly associated with integration of human papillomavirus (HPV) genomes into host chromosomes and subsequent modulation of HPV oncogene expression, which correlates with multi-layered epigenetic changes at the integrated HPV genomes. However, the process of integration itself and dysregulation of host gene expression at sites of integration in our model of HPV16 integrant clone natural selection has remained enigmatic. We now show, using a state-of-the-art 'HPV integrated site capture' (HISC) technique, that integration likely occurs through microhomology-mediated repair (MHMR) mechanisms via either a direct process, resulting in host sequence deletion (in our case, partially homozygously) or via a 'looping' mechanism by which flanking host regions become amplified. Furthermore, using our 'HPV16-specific Region Capture Hi-C' technique, we have determined that chromatin interactions between the integrated virus genome and host chromosomes, both at short- (<500 kbp) and long-range (>500 kbp), appear to drive local host gene dysregulation through the disruption of host:host interactions within (but not exceeding) host structures known as topologically associating domains (TADs). This mechanism of HPV-induced host gene expression modulation indicates that integration of virus genomes near to or within a 'cancer-causing gene' is not essential to influence their expression and that these modifications to genome interactions could have a major role in selection of HPV integrants at the early stage of cervical neoplastic progression.

Remdesivir-related cost-effectiveness and cost and resource use evidence in COVID-19: a systematic review.

BACKGROUND: The coronavirus disease 2019 (COVID-19) pandemic has been a global health emergency since December 2019, leading to millions of deaths worldwide and placing significant pressures, including economic burden, on individual patients and healthcare systems. As of February 2022, remdesivir is the only US Food and Drug Administration (FDA)-approved treatment for severe COVID-19. This systematic literature review (SLR) aimed to summarise economic evaluations, and cost and resource use (CRU) evidence related to remdesivir during the COVID-19 pandemic. METHODS: Searches of MEDLINE, Embase the International Health Technology Assessment (HTA) database, reference lists, congresses and grey literature were performed in May 2021. Articles were reviewed for relevance against pre-specified criteria by two independent reviewers and study quality was assessed using published checklists. RESULTS: Eight studies reported resource use and five reported costs related to remdesivir. Over time, the prescription rate of remdesivir increased and time from disease onset to remdesivir initiation decreased. Remdesivir was associated with a 6% to 21.3% decrease in bed occupancy. Cost estimates for remdesivir ranged widely, from $10 to $780 for a 10-day course. In three out of four included economic evaluations, remdesivir treatment scenarios were cost-effective, ranging from ~ 8 to ~ 23% of the willingness-to-pay threshold for the respective country. CONCLUSIONS: Economic evidence relating to remdesivir should be interpreted with consideration of the broader clinical context, including patients' characteristics and the timing of its administration. Nonetheless, remdesivir remains an important option for physicians in aiming to provide optimal care and relieve pressure on healthcare systems through shifting phases of the pandemic.

Sex-Specific Differences in Patients With Psoriatic Arthritis: A Systematic Review.

OBJECTIVE: A systematic review of published literature was conducted to collate evidence on sex-specific differences in clinical characteristics, disease activity, and patient-reported outcomes (PROs) in psoriatic arthritis (PsA), including response to treatment. METHODS: Searches of MEDLINE, Embase, and the Cochrane Database of Systematic Reviews were performed in November 2020 for observational studies of adults with PsA reporting outcomes by sex (published from January 1, 2015, to November 13, 2020). In addition, hand searches of systematic literature reviews and (network) metaanalysis bibliographies were performed. Searches of ClinicalTrials.gov and congress abstracts from the European Alliance of Associations for Rheumatology, the American College of Rheumatology (ACR), and the American Academy of Dermatology (2019-2020) were also carried out. Eligible studies with 100 or more patients prespecified a comparison by sex and reported clinical characteristics and/or disease activity. Data extracted included patient characteristics, study design, baseline clinical characteristics, and disease activity results, including PROs. RESULTS: Database searching yielded 3283 unique records; 31 publications of 27 unique studies were included. The review found generally higher rates of peripheral disease in women, including higher tender joint counts. There was some evidence of more axial disease in men, plus greater skin disease burden. There were consistently no differences in Dermatology Life Quality Index scores, though across other PROs, women had worse scores, including pain and fatigue. Women had poorer responses to treatment, indicated by outcome measures such as ACR responses and minimal disease activity. CONCLUSION: This review indicates that important differences exist between the sexes in PsA. However, the limited evidence for this conclusion underlines the need for additional research in this area.

Epidemiology and economic burden of amyotrophic lateral sclerosis in the United States: a literature review.

Objective: This review sought to gain a comprehensive, up-to-date understanding of the epidemiology and cost and healthcare resource use (HCRU) burden of amyotrophic lateral sclerosis (ALS) in the US, at a patient and national level. Methods: A targeted literature review (TLR) to identify epidemiological evidence (prevalence, incidence, mortality, survival), and systematic literature review (SLR) to identify cost and HCRU data published since January 2016, were performed. MEDLINE databases and Embase searches were conducted in January 2021. Key congresses (2019-2020) and bibliographies of relevant SLRs were hand-searched. Two high-quality SLRs were reviewed for additional cost data published between January 2001-2015. Registry and database studies were prioritized for epidemiological evidence. To allow comparison between studies in this publication, only evidence from the US was considered, with costs inflated to the 2020/2021 cost-year and converted to US dollars. Results: Eight studies from the epidemiology TLR, and eighteen from the cost and HCRU SLR, were extracted. Reported ALS incidence in the US was ∼1.5 per 100,000 person-years, and point prevalence ranged from 3.84-5.56 per 100,000 population. Total US national costs spanned ∼$212 million-∼$1.4 billion USD/year, and variably consisted of direct costs associated with HCRU and indirect costs. Conclusions: The national cost of ∼$1.02 billion USD/year (estimated using a prevalence of 16,055 cases) best aligns with prevalence estimates found in the TLR (equating to ∼13,000-18,000 cases). However, large-scale, population-based studies are necessary to precisely assess US epidemiology of ALS and capture all costs needed to inform cost-effectiveness models and resource planning.

Burden and Treatment of Achondroplasia: A Systematic Literature Review.

BACKGROUND: Achondroplasia is the most common form of skeletal dysplasia. Recent advances in therapeutic options have highlighted the need for understanding the burden and treatment landscape of the condition. This systematic literature review (SLR) aimed to identify health-related quality of life (HRQoL)/utilities, healthcare resource use (HCRU), costs, efficacy, safety and economic evaluation data in achondroplasia and to identify gaps in the research. METHODS: Searches of MEDLINE, Embase, the University of York Centre for Reviews and Dissemination (CRD), the Cochrane Library and grey literature were performed. Articles were screened against pre-specified eligibility criteria by two individuals and study quality was assessed using published checklists. Additional targeted searches were conducted to identify management guidelines. RESULTS: Fifty-nine unique studies were included. Results demonstrated a substantial HRQoL and HCRU/cost-related burden of achondroplasia on affected individuals and their families throughout their lifetimes, particularly in emotional wellbeing and hospitalisation costs and resource use. Vosoritide, growth hormone (GH) and limb lengthening all conferred benefits for height or growth velocity; however, the long-term effects of GH therapy were unclear, data for vosoritide were from a limited number of studies, and limb lengthening was associated with complications. Included management guidelines varied widely in their scope, with the first global effort to standardise achondroplasia management represented by the International Achondroplasia Consensus Statement published at the end of 2021. Current evidence gaps include a lack of utility and cost-effectiveness data for achondroplasia and its treatments. CONCLUSIONS: This SLR provides a comprehensive overview of the current burden and treatment landscape for achondroplasia, along with areas where evidence is lacking. This review should be updated as new evidence becomes available on emerging therapies.

Readability of CAMHS clinical letters.

BACKGROUND: Sending clinical letters to patients is common practice in CAMHS. Ease of reading and understanding is important for patients. Readability formulae are feasible and quick ways to assess this. METHOD: Clinical letters sent to patients were analysed for readability and whether they reached a preset threshold. Factors influencing readability were investigated. RESULTS:   Most letters were less easily readable than is appropriate. Letters written directly to patients were more readable than copied letters. CONCLUSIONS: Patients sometimes receive letters that are unlikely to be easily readable. Word processing packages contain readability formulae that could be used to check and improve readability of letters.

The burden of disease in early schizophrenia - a systematic literature review.

BACKGROUND: Schizophrenia is a heterogeneous disorder with a burden that can vary greatly depending on the severity and the duration. Previous research has suggested that patients in the earlier stages of schizophrenia (typically first-episode schizophrenia) benefit from effective early treatment, however, a comprehensive review of the burden specifically in this population has not been undertaken. A systematic literature review was therefore conducted to characterize the clinical, economic, and humanistic burden, as reported in naturalistic studies of schizophrenia populations specifically at an early stage of disease in comparison with healthy controls, patients with chronic schizophrenia, and patients with other psychiatric disorders. METHODS AND MATERIALS: Searches were conducted in MEDLINE, MEDLINE In-Process, Embase, PsycINFO, and EconLit databases for records published between January 2005 and April 2019, and of relevant conference abstracts published between January 2014 and May 2019. Data were extracted from relevant publications and subjected to qualitative evaluation. RESULTS: Fifty-two publications were identified for inclusion and revealed a considerable burden for early schizophrenia with regards to mortality, psychiatric comorbidities such as substance abuse and depression, poor social functioning, and unemployment. Comparisons with chronic schizophrenia suggested a greater burden with longer disease duration, while comparisons with other psychiatric disorders were inconclusive. This review uncovered various gaps in the available literature, including limited or no data on incarcerations, caregiver burden, and costs associated with early schizophrenia. CONCLUSIONS: Overall, the burden of schizophrenia is apparent even in the early stages of the disease, although further research is required to quantify the burden with chronic schizophrenia and other psychiatric disorders.