BACKGROUND:There is insufficient data to inform the management of dolutegravir failure, with the WHO and various countries adopting different approaches, underscoring the need for an evidence-based management approach. METHODS:The Ndovu study is a large multi-country cohort, with a nested randomised controlled trial (RCT), enrolling 6,600 people living with HIV (PLWH) with viral load (VL) of ≥1000 copies/ml after at least 6 months of dolutegravir. Participants aged ≥ 1 year, including pregnant women, will be followed up for 12 months with enhanced adherence counselling (EAC) provided monthly. Viral load (VL) testing will be conducted every 3 months and drug resistance testing conducted if VL ≥ 200 copies/ml. Three hundred and sixty-two participants aged ≥15 years and 30 participants aged 3-14 years with major dolutegravir-associated drug resistant mutations (DRMs) will be enrolled into the RCT and randomised to switch to ritonavir boosted darunavir (DRV/r) or continue with dolutegravir with follow-up for 12 months. VL will be measured at 1, 3, 6 and 12 months and tenofovir levels assessed on dried blood spots at month 1 and month 6. The primary outcome of the cohort is the proportion of participants achieving viral load <200 copies/ml by month 12 and the primary endpoint of the RCT is viral load <200copies/ml at 6 months using a modified FDA snap shot algorithm. Secondary endpoints are DRM patterns associated with non-suppression, level of adherence associated with suppression as well as participant and provider experiences of staying on DTG versus switching to DRV/r. The RCT primary efficacy analysis will be conducted on the Intent-to-Treat Exposed (ITT-E) population and will compare the difference in the proportion of participants with viral load <200 copies/ml 6 months after randomisation between the treatment arms stratified by the randomisation stratification factors. This study is registered at ClinicalTrials.gov, NCT06762054 (cohort) and NCT06747507 (RCT) and enrollment into the cohort started in March 2025. CONCLUSION:The Ndovu study will address critical gaps in the management of DTG failure including the emergence, determinants and implications of DTG resistance. Further, it will evaluate the optimal ART regimens to use in the setting of DTG resistance in adults and children.
Histopathologically detected extranodal extension leads to upstaging and treatment escalation in head and neck squamous cell carcinoma. There is considerable variation in the prevalence of histopathologically detected extranodal extension in comparable studies. The Head and Neck Cancer International Group, which includes 23 organisations managing patients with head and neck cancer, identified several challenges in evaluating histopathologically detected extranodal extension. Thus, the Head and Neck Consensus Language for Ease and Reproducibility (HN-CLEAR) and its global stakeholders prioritised developing diagnostic criteria and uniform terminology for histopathologically detected extranodal extension. The histopathologically detected extranodal extension working group established by WHO, International Collaboration on Cancer Reporting, American Joint Committee on Cancer, Union for International Cancer Control, North American Society of Head and Neck Pathology, and American Academy of Oral and Maxillofacial Pathology committees undertook consensus deliberations using scanned whole slides and a PRISMA literature review-based scoping questionnaire. The guidelines were tested by 30 additional pathologists across six continents and strengthened with prescriptive diagnostic criteria and unifying terminology based on the inter-rater concordance analyses. This Review generates practically useful consensus diagnostic recommendations and aligned terminology for addressing the gaps in the histopathologically detected extranodal extension literature. The recommendations can be used globally and cater to all levels of medical resources, practices, and experiences, thus ensuring equitable patient care.
Introduction:Allergic Rhinitis (AR) is an IgE- mediated inflammatory disease of the nasal mucosa. While the diagnosis mainly relies on a typical clinical history and physical examination, the evaluation of eosinophils in nasal smears is considered a direct marker of inflammation and can play a role in the diagnosis and monitoring of treatment response. The aim of this study was to evaluate the levels of nasal eosinophils among patients with AR, and to correlate these levels with disease severity and frequency. Material and methods:This was a descriptive cross-sectional study conducted at a tertiary referral hospital in Kenya from November 2022 to January 2023. Patients were diagnosed with AR using the Score for Allergic Rhinitis (SFAR) questionnaire. A Total Nasal Symptom Score (TNSS) questionnaire was administered to evaluate for nasal symptoms and assign severity scores. The patients were categorized according to the Allergic Rhinitis and its Impact on Asthma (ARIA) guidelines into either intermittent or persistent allergic rhinitis groups, and further sub-classified into mild, or moderate-to-severe AR. Nasal smears were collected to quantify eosinophil counts. Results:The study included 73 patients comprising 35 (47.9%) males and 38 (52.1%) females. The median age of the participants was 19 years (Interquartile Range 9-38), with an age range of 5-84 years. Most patients presented with intermittent symptoms (58.9%) and moderate-to-severe disease (61.6%). Pathological levels of eosinophils were found in 15 patients (20.5%). However, there was no statistically significant correlation between the level of nasal eosinophilia and either disease severity (p = 0.23) or symptom frequency (p = 0.80). Conclusion:In this study, nasal eosinophils counts did not correlate with the severity or frequency of AR as defined by the ARIA classification. These findings suggest that while the presence of nasal eosinophilia is useful for confirming the underlying type 2 inflammation in AR, it should not be used as a standalone biomarker to determine disease severity or guide management.
Annually, community-acquired pneumonia (CAP) affects millions of individuals worldwide, resulting in more than 200 000 hospital admissions in England alone. CAP is a major cause of morbidity and mortality. Previous studies have explored the causes, risk factors, and the clinical course of CAP in detail. Sepsis and respiratory failure are important well-recognised consequences of progressive infection and have been researched extensively. In this Review, we focus on complications of CAP beyond the natural history of the condition. These sequelae of CAP often have long-term implications for patients and encompass a wide range of physical, functional, and psychosocial impairments, including reduced functional ability and persistent symptoms that adversely affect quality of life. Research on complications after CAP has increased since the COVID-19 pandemic. A growing body of literature informs clinical trials and guides clinical management. We explore the recovery trajectory and discuss updates in the management of post-CAP pleural infection, the established risk of cardiovascular events after CAP, and association of CAP with cognitive impairment and lung cancer. Finally, we conclude that improved long-term data, standardisation, and targeted research are needed to understand, prevent, and manage these outcomes effectively.
