[Posted 29/May/2023]

AUDIENCE: Gastroenterology, Oncology, Internal Medicine

KEY FINDINGS: The findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.

DETAILS: Authors used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. They identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC. iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Hamdan, F. H., Abdelrahman, A. M., Kutschat, A. P., et al. (2023). Interactive Enhancer Hubs (iHUBs) Mediate Transcriptional Reprogramming And Adaptive Resistance In Pancreatic Cancer. Gut. 2023; 72(6): 1174-1185. Published: June, 2023. DOI: 10.1136/gutjnl-2022-328154.

A Systematic Review and Meta-analysis.

[Posted 17/Oct/2025]

AUDIENCE: Gastroenterology, Internal Medicine, Oncology

KEY FINDINGS: ESD is a safe and effective option for managing RNDLs with a low recurrence rate. Adverse events such as postprocedural perianal pain, postprocedural bleeding, and anal stenosis seem to be more common compared with colorectal ESD done for more proximal lesions. However, these can typically be managed conservatively or with minimally invasive endoscopic techniques.

BACKGROUND: Endoscopic submucosal dissection (ESD) is a superior, minimally invasive technique compared with other snare-based endoscopic resection techniques for rectal neoplasms extending to the dentate line (RNDLs). However, performing a successful ESD in the anal canal can be challenging due to vascularity and limited scope stability. In this meta-analysis, we aim to evaluate the safety and efficacy of ESD for RNDLs.

DETAILS: Authors performed a comprehensive electronic database search from January 2005 through January 2024 for studies evaluating outcomes of ESD performed for managing RNDLs. Pooled proportions were calculated using random-effect models. Heterogeneity was evaluated using I2 and Q statistics. Data were extracted from 11 studies comprising 496 patients. The pooled en bloc resection rates were 93.60% (95% CI = 90.70-95.70). The pooled R0 resection rate was 80.60% (95% CI = 70.50-87.80). The pooled recurrence rate was 4.00% (95% CI = 2.40-6.50). There was no evidence of significant heterogeneity calculated using the Q test and I2 statistic. The main adverse events were anal pain, postprocedural bleeding, and anal stricture with pooled rates of 20.20% (95% CI = 14.80-26.90), 8.20% (95% CI = 4.70-14.0), and 3.50% (95% CI = 2.10-5.70), respectively.

Copyright © Wolters Kluwer Health, Inc. All rights reserved.

Source: Gopakumar, H., Dahiya, D., Draganov, P. V., et al. Safety and Efficacy of Endoscopic Submucosal Dissection for Rectal Neoplasms Extending to the Dentate Line: A Systematic Review and Meta-analysis. Journal of Clinical Gastroenterology. 2025; 59(10): 954-963. Published: November/December, 2025. DOI: 10.1097/MCG.0000000000002090.

A Cohort Study Investigating Adherence of Dose and Duration to UK Clinical Guidelines

[Posted 14/Oct/2025]

AUDIENCE: Psychiatry, Family Medicine

KEY FINDINGS: This study highlights how antipsychotic prescribing in dementia is discordant with current NICE guidelines on both duration and dose. More than half of those who discontinued their treatment then restarted treatment. These findings emphasise a persistent gap between clinical guidelines and real-world prescribing, underscoring the need for interventions that prioritise safety and person-centred dementia care.

BACKGROUND: In the UK, it is recommended by the National Institute for Health and Care Excellence (NICE) that if antipsychotics are initiated in people living with dementia, treatment should be at the lowest dose for the shortest time possible (1-3 months). In this study, authors aimed to investigate how dose and duration of antipsychotic medication adhere to UK clinical guidelines and explore treatment restart details in those who stop treatment.

DETAILS: Authors did a retrospective cohort study using longitudinal UK primary care data from the IQVIA Medical Research Database. Authors included people living with dementia aged 60-85 years who received their first antipsychotic prescription between Jan 1, 2000, and Dec 31, 2023. Individuals with any previous antipsychotic prescriptions in their records more than 1 year before a dementia diagnosis and those who had missing social deprivation information were excluded from the study. Duration of first and subsequent antipsychotic treatment episodes, medication dosage, and treatment discontinuation and reinitiation rates were investigated. Duration and discontinuation were defined by grouping consecutive prescriptions into treatment episodes using the waiting time distribution method (80% inter-arrival density, 59 days). Daily doses were derived from strength and frequency information and categorised as low or moderate or high based on established minimum effective dose equivalences. People with lived experience of dementia care contributed throughout this project, shaping the research question and advising on interpretation and dissemination strategies. In the dataset search, authors identified 108,910 people with a record indicating dementia at any time. In total, 99,091 cases were excluded (ie, individuals with no antipsychotic prescription between the ages of 60 and 85 years between 2000 and 2023, a previous history of antipsychotics, missing deprivation information, or only one eligible prescription). Authors included 9819 people living with dementia aged 60-85 years who received their first antipsychotic prescription between 2000 and 2023 in the study. 5310 (54.1%) were female and 4509 (45.9%) were male, with a mean age of 77.1 years (SD 5.6 years), and ethnicity data were not available. The first treatment episode lasted a median of 7 months (IQR 6.6-8.7), exceeding NICE guidelines of 1-3 months and 18.1% [95% CI 17.4-18.9]) were initiated on a prescription above the minimum effective dose (ie, low dose). Of the 1781 participants who started on a moderate or high dose, 519 (29.1%) had a moderate or high dose in all quarters of the first year of treatment. 1 year after treatment initiation, 5136 (78.3%) of 6559 eligible individuals remained on medication (48.9% [95% CI 47.7-50.1] on low dose, 14.8% [13.9-15.6] on moderate or high dose of haloperidol, olanzapine, quetiapine or risperidone; and 14.6% [13.8-15.5] on other antipsychotics). Of the 5547 individuals eligible to restart treatment after initial discontinuation, 3106 (56%) restarted with a median treatment duration of 2.6 months (IQR 0.0-9.9).

Copyright © Elsevier Ltd. All rights reserved.

Source: Smsith, H. C., Petersen, I., Hayes, J. F., et al. (2024). Antipsychotic Prescriptions in People With Dementia in Primary Care: A Cohort Study Investigating Adherence of Dose and Duration to UK Clinical Guidelines. The Lancet Psychiatry. 2025; 12(10): 758-767. Published: October, 2025. DOI: 10.1016/S2215-0366(25)00261-5.

[Posted 9/Oct/2025]

AUDIENCE: Gastroenterology, Internal Medicine

KEY FINDINGS: Elevated DUOX2 signalling contributes to epithelial barrier dysfunction, microbiome alterations and subclinical inflammation. Butyrate and HDAC inhibitors reversed these effects, indicating that DUOX2 may be a therapeutic target in IBD.

BACKGROUND: Inflammatory bowel diseases (IBDs) are characterised by dysbiosis and a leaky gut. The NADPH oxidase dual oxidase 2 (DUOX2) is upregulated in patients with IBD, yet its role in driving the disease remains unclear. Authors interrogated the functional consequences of epithelial DUOX2 activity for the host and microbiome.

DETAILS: DUOX2 function was studied in mice with epithelial-specific DUOX2 overactivation (vTLR4), inactivation (vTLR4 DUOXA IEC-KO) and wild-type controls. Authors assessed the effect of dysbiosis on DUOX2 signalling and intestinal permeability (FITC-dextran, serum zonulin, bacterial translocation) with germ-free (GF) mice engrafted with IBD or healthy microbiota. RNA sequencing of colonic mucosa and microbiota and faecal metabolomics were used to characterise the host-microbe interface. Mechanistic studies were conducted in mouse colonoids, IBD biopsies and patient serum samples. DUOX2 activity increased permeability and bacterial translocation and induced subclinical inflammation in vTLR4 mice. GF vTLR4 mice had increased DUOX2 activity and permeability but no subclinical inflammation. In patients with IBD, DUOX2 expression was positively associated with plasma zonulin levels and negatively associated with ZO-1 expression. Engraftment of GF mice with IBD stool increased DUOX2 activity and triggered low-grade inflammation and permeability defects in mice. DUOX2 activity functionally altered the microbiome, reduced butyrate metabolism and promoted proinflammatory and pro-oncogenic bacterial metabolites. Butyrate and histone deacetylase (HDAC) inhibitors blocked DUOX2 activation and reversed its effects.

Copyright © BMJ Publishing Group Ltd & British Society of Gastroenterology. All rights reserved.

Source: Hazime, H., Ducasa, G. M., Santander, A. M., et al. (2025). DUOX2 Activation Drives Bacterial Translocation and Subclinical Inflammation in IBD-Associated Dysbiosis. dysbiosisGut. 2025; 74: 1589-1601. Published: October, 2025. DOI: 10.1136/gutjnl-2024-334346.

A Retrospective Repeated Cross-Sectional Study

[Posted 3/Oct/2025]

AUDIENCE: Family Medicine, Infectious Disease

KEY FINDINGS: Medicare beneficiaries aged 65 years and older with HIV in the USA were more likely to receive opioid prescriptions and have OUD indicators than matched beneficiaries without HIV. Findings could help guide clinical opioid prescription guidelines and public health surveillance among this vulnerable ageing population.

BACKGROUND: There is longstanding concern that people with HIV receive prescription opioids at higher rates and have a disproportionate burden of opioid use disorder (OUD) compared with their counterparts without HIV. We aimed to evaluate trends of opioid prescriptions and indicators of OUD in an understudied but growing population of older adults with HIV.

DETAILS: For this retrospective repeated cross-sectional study, authors constructed annual cohorts through a nationally representative sample of fee-for-service Medicare beneficiaries aged 65 years and older in the USA with Part D coverage (ie, prescription drug) enrolled between Jan 1, 2008, and Dec 31, 2021. Beneficiaries were eligible for inclusion in each cross-sectional cohort if they had reached the age of 65 years by Jan 1 of the calendar year and had 1 year of continuous Medicare enrolment in Part A (inpatient hospital care), B (outpatient care), and D. Beneficiaries with HIV were matched in a 1:3 ratio to beneficiaries without HIV on age, sex, race or ethnicity, US state, and dual eligibility status (Medicare and Medicaid). The main outcomes were receipt of at least one opioid prescription and any indicator of OUD (ie, formal diagnosis, medication for OUD, or opioid-related or emergency department visits) during each calendar year. Generalised estimating equations were used to estimate odds ratios (ORs) of each outcome, comparing matched beneficiaries with or without HIV. Due to data availability, our analysis of indicators of OUD was restricted to 2008-16. Across all years, 163,429 beneficiaries with HIV and 490,287 beneficiaries without HIV were included (475,516 [72.7%] were male, 178,200 [27.3%] were female; 305,776 [46.8%] were non-Hispanic White, 238,172 [36.4%] were Black [or African American], 84,128 [12.9%] were Hispanic, 8964 [1.4%] were Asian or Pacific Islander, and 16,676 [2.6%] were other races or ethnicities). During 2008-21, 57,373 (35.1%) of 163,429 people with HIV and 138,547 (28.3%) of 490,287 people without HIV received at least one opioid prescription. During 2008-16, 2408 (3.1%) of 76,637 people with HIV and 2831 (1.2%) of 229,911 people without HIV had any indicator of OUD. Across all analysed years, beneficiaries with HIV had significantly increased odds of receiving at least one opioid prescription (OR 1.38, 95% CI 1.36-1.39) and having indicators of OUD (2.61, 2.47-2.76) compared with their matched counterparts without HIV.

Copyright © The Author(s). Elsevier Ltd. All rights reserved.

Source: Shiau, S., Drago, F., Kinkade, C. W., et al. (2024). Prescription Opioid Use and Opioid Use Disorder Among Older Adults With HIV in the USA From 2008 to 2021: A Retrospective Repeated Cross-Sectional Study. The Lancet Primary Care. 2025; 1(3): 100017. Published: September, 2025. DOI: 10.1016/j.lanprc.2025.100017.

A Systematic Review and Individual Patient Data Meta-Analysis

[Posted 15/Sep/2025]

AUDIENCE: Infectious Disease, Pediatric

KEY FINDINGS: Regardless of malaria transmission intensity and age group, a single dose of 0.25 mg/kg primaquine is safe and efficacious for reducing P falciparum transmission. These findings underscore the need for primaquine formulations suitable for young children, and also provide supportive evidence to expand the use of single low-dose primaquine in regions with a moderate-to-high transmission rate that are threatened by artemisinin partial resistance.

BACKGROUND: Adding a single dose of primaquine to artemisinin-based combination therapy (ACT) for the treatment of falciparum malaria can reduce the transmission of Plasmodium falciparum and could limit the spread of artemisinin partial resistance, including in Africa, where the disease burden is greatest. Authors aimed to compare the safety and efficacy of single-dose primaquine plus ACT between young children (aged <5 years) and older children (aged 5 years to <15 years) and adults (aged >=15 years), and between low and moderate-to-high transmission areas.

DETAILS: For this systematic review and individual patient data meta-analysis, authors searched PubMed, Embase, Web of Science, Cochrane Central Register of Controlled Trials, WHO Global Index Medicus, OpenGrey.eu, ClinicalTrials.gov, and the WHO International Clinical Trials Registry Platform, from database inception to April 3, 2024, with no language restrictions. Authors included prospective studies on efficacy against falciparum malaria that enrolled at least one child younger than 15 years and involved a study group given a single dose of primaquine (<=0.75 mg/kg) plus ACT. Studies involving mass drug administration, healthy volunteers, or patients with severe malaria or mixed (with non-falciparum) infections were excluded. For inclusion in the efficacy analysis, data on transmission potential (as determined by gametocytaemia, infectivity, or both) at enrolment and follow-up (day 3, day 7, or day 14) were required; the safety analysis required data on haemoglobin concentrations or haematocrit values at enrolment and at one or more follow-up visits by day 7, any data on adverse events, or both. After independent screening of the search results by two reviewers, the investigators of eligible studies were invited to contribute individual patient data. Authors quantified day 7 gametocyte carriage, probability of infecting a mosquito, decreases (>25%) in haemoglobin concentration associated with anaemia, and adverse events until day 28 using regression analyses, with random study-site intercepts to account for clustered data. These analyses were registered with PROSPERO, CRD42021279363 (safety) and CRD42021279369 (efficacy). Of 5697 records identified by the search, 30 studies were eligible for analysis. Of these, individual patient data were shared for 23 studies, including 6056 patients from 16 countries: 1171 (19.3%) young children (aged <5 years), 2827 (46.7%) older children (aged 5 years to <15 years), and 2058 (34.0%) adults (aged >=15 years). Adding a single low dose of primaquine (0.2-0.25 mg/kg) to ACTs reduced day 7 gametocyte positivity (adjusted odds ratio [aOR] 0.34, 95% CI 0.22-0.52; p<0.001) and infectivity to mosquitoes over time (aOR per day 0.02, 0.01-0.07, p<0.001). No difference was found in the effect of single low-dose primaquine both on gametocyte positivity in young children compared with older children (1.08, 0.52-2.23; p=0.84) and adults (0.50, 0.20-1.25; p=0.14) and between low-transmission and moderate-to-high transmission settings (1.07, 0.46-2.52; p=0.86), and on infectivity to mosquitoes in young children compared with older children (1.36, 0.07-27.71; p=0.84) and adults (0.31, 0.01-8.84; p=0.50) and between low-transmission and moderate-to-high transmission settings (0.18, 0.01-2.95; p=0.23). Gametocyte clearance was also similar for different ACTs (dihydroartemisinin-piperaquine vs artemether-lumefantrine) when combined with a primaquine target dose of 0.25 mg/kg (1.56, 0.65-3.79; p=0.32 at day 7). However, patients given a primaquine dose of less than 0.2 mg/kg with dihydroartemisinin-piperaquine were more likely to have gametocytaemia than those treated with artemether-lumefantrine (5.68, 1.38-23.48; p=0.016 at day 7). There was no increase in anaemia-associated declines in haemoglobin concentration (>25%) at a primaquine dose of 0.25 mg/kg, regardless of age group, transmission setting, and glucose-6-phosphate dehydrogenase status. The risks of adverse events of grade 2 or higher and of serious adverse events were similar between primaquine and no-primaquine groups, including in young children.

Copyright © The Author(s). Published by Elsevier Ltd. All rights reserved.

Source: Yilma, D., Stepniewska, K., Bousema, T., et al. (2024). Safety and Efficacy of Single-Dose Primaquine to Interrupt Plasmodium Falciparum Malaria Transmission in Children Compared With Adults: A Systematic Review and Individual Patient Data Meta-Analysis. The Lancet Infectious Diseases. 2025; 25(9): 965-976. Published: September, 2025. DOI: 10.1016/S1473-3099(25)00078-7.