Effectiveness and Safety of Adalimumab Biosimilar SB5 in IBD:Outcomes in Originator to SB5 Switch, Double Biosimilar Switch and Bio-Naieve SB5 Observational Cohorts

BACKGROUND AND AIMS: Multiple adalimumab [ADA] biosimilars are now approved for use in inflammatory bowel disease [IBD]; however, effectiveness and safety data remain scarce. We aimed to investigate long-term outcomes of the ADA biosimilar SB5 in IBD patients following a switch from the ADA originator [SB5-switch cohort] or after start of SB5 [SB5-start cohort]. METHODS: We performed an observational cohort study in a tertiary IBD referral centre. All IBD patients treated with Humira underwent an elective switch to SB5. We identified all these patients in a biological prescription database that prospectively registered all ADA start and stop dates including brand names. Data on IBD phenotype, C-reactive protein [CRP], drug persistence, ADA drug and antibody levels, and faecal calprotectin were collected. RESULTS: In total, 481 patients were treated with SB5, 256 in the SB5-switch cohort (median follow-up: 13.7 months [IQR 8.6–15.2]) and 225 in the SB5-start cohort [median follow-up: 8.3 months [4.2–12.8]). Of the SB5-switch cohort, 70.8% remained on SB5 beyond 1 year; 90/256 discontinued SB5, mainly due to adverse events [46/90] or secondary loss of response [37/90]. In the SB5-start cohort, 81/225 discontinued SB5, resulting in SB5-drug persistence of 60.3% beyond 1 year. No differences in clinical remission [p = 0.53], CRP [p = 0.80], faecal calprotectin [p = 0.40] and ADA trough levels [p = 0.55] were found between baseline, week 26 and week 52 following switch. Injection site pain was the most frequently reported adverse event. CONCLUSION: Switching from ADA originator to SB5 appeared effective and safe in this study with over 12 months of follow-up

Motivations and barriers to uptake and use of female-initiated, biomedical HIV prevention products in sub-Saharan Africa: an adapted meta-ethnography

Abstract: Background: Women bear a disproportionate burden of HIV throughout the world prompting extensive research into HIV prevention products for women which has met with varied success. With an aim of informing future policy and programming, this review examines the barriers and motivations to the uptake and use of female initiated products in sub-Saharan countries. Methods: We conducted a systematic review as an adapted meta-ethnography of qualitative data focused on actual use of products. After deduplication, 10,581 and 3861 papers in the first and second round respectively were screened. Following the PRISMA guidance, 22 papers were selected and synthesized using Malpass’s definitions of first, second, and third order constructs. First order constructs, consisting of participant data published in the selected papers, were extracted and categorised by second and third order constructs for analysis. A weight of evidence review was conducted to compare and assess quality across the papers. Results: The 22 papers selected span 11 studies in 13 countries. We derived 23 s order constructs that were translated into seven overarching third order constructs: Sexual Satisfaction, Trust, Empowerment and Control, Personal Well-being, Product use in the social-cultural environment, Practical Considerations, Risk Reduction, and Perceptions of Efficacy. Relationships and trust were seen to be as or more important for product use as efficacy. These constructs reveal an inherent inter-relationality where decision making around HIV prevention uptake and use cannot be binary or mono-faceted, but rather conducted on multiple levels. We developed a framework illustrating the central and proximal natures of constructs as they relate to the decision-making process surrounding the use of prevention products. Conclusions: Health systems, structural, and individual level HIV prevention interventions for women should adopt a holistic approach. Interventions should attend to the ways in which HIV prevention products can serve to reduce the likelihood of HIV transmission, as well as help to protect partnerships, enhance sexual pleasure, and take into account woman’s roles in the social environment. Stigma, as well as sexuality, is likely to continue to influence product uptake and use and should be prominently taken into account in large-scale interventions. Trial registration: Not applicable

Cell Cycle Genes Are the Evolutionarily Conserved Targets of the E2F4 Transcription Factor

Maintaining quiescent cells in G0 phase is achieved in part through the multiprotein subunit complex known as DREAM, and in human cell lines the transcription factor E2F4 directs this complex to its cell cycle targets. We found that E2F4 binds a highly overlapping set of human genes among three diverse primary tissues and an asynchronous cell line, which suggests that tissue-specific binding partners and chromatin structure have minimal influence on E2F4 targeting. To investigate the conservation of these transcription factor binding events, we identified the mouse genes bound by E2f4 in seven primary mouse tissues and a cell line. E2f4 bound a set of mouse genes that was common among mouse tissues, but largely distinct from the genes bound in human. The evolutionarily conserved set of E2F4 bound genes is highly enriched for functionally relevant regulatory interactions important for maintaining cellular quiescence. In contrast, we found minimal mRNA expression perturbations in this core set of E2f4 bound genes in the liver, kidney, and testes of E2f4 null mice. Thus, the regulatory mechanisms maintaining quiescence are robust even to complete loss of conserved transcription factor binding events

Heterozygous Variants in KMT2E Cause a Spectrum of Neurodevelopmental Disorders and Epilepsy.

We delineate a KMT2E-related neurodevelopmental disorder on the basis of 38 individuals in 36 families. This study includes 31 distinct heterozygous variants in KMT2E (28 ascertained from Matchmaker Exchange and three previously reported), and four individuals with chromosome 7q22.2-22.23 microdeletions encompassing KMT2E (one previously reported). Almost all variants occurred de novo, and most were truncating. Most affected individuals with protein-truncating variants presented with mild intellectual disability. One-quarter of individuals met criteria for autism. Additional common features include macrocephaly, hypotonia, functional gastrointestinal abnormalities, and a subtle facial gestalt. Epilepsy was present in about one-fifth of individuals with truncating variants and was responsive to treatment with anti-epileptic medications in almost all. More than 70% of the individuals were male, and expressivity was variable by sex; epilepsy was more common in females and autism more common in males. The four individuals with microdeletions encompassing KMT2E generally presented similarly to those with truncating variants, but the degree of developmental delay was greater. The group of four individuals with missense variants in KMT2E presented with the most severe developmental delays. Epilepsy was present in all individuals with missense variants, often manifesting as treatment-resistant infantile epileptic encephalopathy. Microcephaly was also common in this group. Haploinsufficiency versus gain-of-function or dominant-negative effects specific to these missense variants in KMT2E might explain this divergence in phenotype, but requires independent validation. Disruptive variants in KMT2E are an under-recognized cause of neurodevelopmental abnormalities

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK.

BACKGROUND: A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. METHODS: This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. FINDINGS: Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0-75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4-97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8-80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3-4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. INTERPRETATION: ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials. FUNDING: UK Research and Innovation, National Institutes for Health Research (NIHR), Coalition for Epidemic Preparedness Innovations, Bill & Melinda Gates Foundation, Lemann Foundation, Rede D'Or, Brava and Telles Foundation, NIHR Oxford Biomedical Research Centre, Thames Valley and South Midland's NIHR Clinical Research Network, and AstraZeneca

Safety and efficacy of the ChAdOx1 nCoV-19 vaccine (AZD1222) against SARS-CoV-2: an interim analysis of four randomised controlled trials in Brazil, South Africa, and the UK

Background A safe and efficacious vaccine against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), if deployed with high coverage, could contribute to the control of the COVID-19 pandemic. We evaluated the safety and efficacy of the ChAdOx1 nCoV-19 vaccine in a pooled interim analysis of four trials. Methods This analysis includes data from four ongoing blinded, randomised, controlled trials done across the UK, Brazil, and South Africa. Participants aged 18 years and older were randomly assigned (1:1) to ChAdOx1 nCoV-19 vaccine or control (meningococcal group A, C, W, and Y conjugate vaccine or saline). Participants in the ChAdOx1 nCoV-19 group received two doses containing 5 × 1010 viral particles (standard dose; SD/SD cohort); a subset in the UK trial received a half dose as their first dose (low dose) and a standard dose as their second dose (LD/SD cohort). The primary efficacy analysis included symptomatic COVID-19 in seronegative participants with a nucleic acid amplification test-positive swab more than 14 days after a second dose of vaccine. Participants were analysed according to treatment received, with data cutoff on Nov 4, 2020. Vaccine efficacy was calculated as 1 - relative risk derived from a robust Poisson regression model adjusted for age. Studies are registered at ISRCTN89951424 and ClinicalTrials.gov, NCT04324606, NCT04400838, and NCT04444674. Findings Between April 23 and Nov 4, 2020, 23 848 participants were enrolled and 11 636 participants (7548 in the UK, 4088 in Brazil) were included in the interim primary efficacy analysis. In participants who received two standard doses, vaccine efficacy was 62·1% (95% CI 41·0–75·7; 27 [0·6%] of 4440 in the ChAdOx1 nCoV-19 group vs71 [1·6%] of 4455 in the control group) and in participants who received a low dose followed by a standard dose, efficacy was 90·0% (67·4–97·0; three [0·2%] of 1367 vs 30 [2·2%] of 1374; pinteraction=0·010). Overall vaccine efficacy across both groups was 70·4% (95·8% CI 54·8–80·6; 30 [0·5%] of 5807 vs 101 [1·7%] of 5829). From 21 days after the first dose, there were ten cases hospitalised for COVID-19, all in the control arm; two were classified as severe COVID-19, including one death. There were 74 341 person-months of safety follow-up (median 3·4 months, IQR 1·3–4·8): 175 severe adverse events occurred in 168 participants, 84 events in the ChAdOx1 nCoV-19 group and 91 in the control group. Three events were classified as possibly related to a vaccine: one in the ChAdOx1 nCoV-19 group, one in the control group, and one in a participant who remains masked to group allocation. Interpretation ChAdOx1 nCoV-19 has an acceptable safety profile and has been found to be efficacious against symptomatic COVID-19 in this interim analysis of ongoing clinical trials

Depersonalization and derealization as sequelae of a temporal lobe lesion: a case report

Abstract Background Depersonalization and derealization can occur not just from psychiatric causes but also from various organic etiologies, such as seizures and intracerebral structural abnormalities. However, there have been no previous reported cases to the authors’ knowledge detailing isolated depersonalization and derealization in the absence of clinical seizure activity or other psychiatric pathology, as sequelae of structural intracerebral lesions. Case presentation In this case report, we detail the unique presentation of a 68-year-old woman under the care of palliative medicine who experienced depersonalization and derealization secondary to a metastatic lesion in her temporal lobe, in the parahippocampal gyrus to medial occipitotemporal gyrus region. These symptoms were present in the absence of any clinical seizure activity or other psychiatric symptomatology and largely resolved with the use of steroidal therapy, before returning secondary to disease progression. Conclusions We discuss the relationship among isolated depersonalization and derealization with pathology of the left posterior temporal lobe in the context of this interesting case. This case expands our knowledge of the neurobiology of these phenomena, given the specific localization of the intracerebral pathology and temporal specificity of symptoms relative to tumor growth and treatment course

Quality of End-of-Life Care in Gastrointestinal Cancers: A 13-Year Population-Based Retrospective Analysis in Ontario, Canada

Population-based quality indicators of either aggressive or supportive care at end of life (EOL), especially when specific to a cancer type, help to inform quality improvement efforts. This is a population-based, retrospective cohort study of gastrointestinal (GI) cancer decedents in Ontario from 1 January 2006–31 December 2018, using administrative data. Quality indices included hospitalizations, emergency department (ED) use, intensive care unit admissions, receipt of chemotherapy, physician house call, and palliative home care in the last 14–30 days of life. Previously defined aggregate measures of both aggressive and supportive care at end of life were also used. In our population of 69,983 patients who died of a GI malignancy during the study period, the odds of experiencing aggressive care at EOL remained stable, while the odds of experiencing supportive care at EOL increased. Most of our population received palliative care in the last year of life (n = 65,076, 93.0%) and a palliative care home care service in the last 30 days of life (n = 45,327, 70.0%). A significant number of patients also experienced death in an acute care hospital bed (n = 28,721, 41.0%) or had a new hospitalisation in the last 30 days of life (n = 33,283, 51.4%). The majority of patients received palliative care in the last year of life, and a majority received a palliative care home service within the last 30 days of life. The odds of receiving supportive care at EOL have increased over time. Differences in care exist according to income, age, and rurality