Santhera Pharmaceuticals (Switzerland)

Understanding how the gut microbiome confers immune protection in early life remains a fundamental challenge, particularly in high-infection-burden, underrepresented populations. Here, we analyse longitudinal stool microbiome and illness data from 633 Gambian children aged 7–37 months enroled in a randomised, double-blind iron supplementation trial (NCT02941081). The primary endpoint was correction of iron deficiency anaemia, and the secondary endpoint was diarrhoea incidence and other adverse events; IHAT was non-inferior to ferrous sulphate for iron correction and showed fewer moderate-to-severe diarrhoea episodes. Using 16S rRNA sequencing at three timepoints (Days 1, 15, and 85), we find that children who remained infection-free harboured a consistently higher relative abundance of Prevotella stercorea, a keystone taxon of non-industrialised gut ecologies. In contrast, Escherichia coli and other opportunistic pathogens were enriched in children who developed infections. These taxonomic signatures were temporally stable and embedded within distinct, co-occurring microbial networks. Strikingly, higher P. stercorea abundance was inversely associated with both infection frequency and duration, with the greatest differences observed in children aged 1–2 years, potentially explaining their increased infectious risk. Our findings reveal a Prevotella-dominated enterotype associated with reduced infection risk, with implications for vaccine responsiveness, child survival, and microbiota-targeted interventions in global child health.

Abstract PurposeLeber Hereditary Optic Neuropathy (LHON) is a mitochondrial genetic disorder causing severe, bilateral loss of visual acuity (VA). Idebenone is the only treatment for LHON currently approved in Europe. Due to the rarity of the disease, information about outcome in patients starting treatment >12 months since disease onset in the most recent eye (chronic LHON) is scarce.MethodsThe search for clinical evidence included any published study or conference abstract evaluating oral idebenone at the approved dose of 900 mg/day, in patients with confirmed diagnosis of LHON starting treatment >12 months since disease onset in the most recent eye. Literature search was carried out on Medline, Embase, InsightMeme and Cochrane Libraries up to March 2020.ResultsEvidence for idebenone treatment of chronic LHON is based on four uncontrolled, retrospective case series and one post‐hoc analysis of a randomized controlled study. All studies included patients (n = 4–53) with confirmed primary LHON mutations and evaluated changes in VA with the Early Treatment Diabetic Retinopathy Study (ETDRS) chart. The post‐hoc analysis (n = 53, idebenone:34; placebo:19) assessed efficacy as rate of clinically relevant recovery (CRR; defined as improvement from off‐chart to reading five letters, or improvement of 10 letters) from baseline (BL) after 6‐month therapy. 35.3% of idebenone‐treated versus 10.5% of placebo patients achieved CRR (p = 0.059); by eyes: 23.5% versus 5.3% (p = 0.016). All 4 retrospective studies (n = 4–16) assessed efficacy as average VA improvement (all eyes) from BL after 9 to 12 months of therapy. Improvements ranged from −0.20 to −0.31 logMAR (2–3 ETDRS lines). One retrospective study compared the effect of idebenone in two subgroups according to time from LHON onset (1–5 years, n = 7; >5 years, n = 8) showing no difference between groups.ConclusionsData presented indicates a potential therapeutic effect of idebenone in chronic LHON patients, which may be explained by the reactivation of dysfunctional retinal ganglion cells and deserved further investigation.

Although thousands of breast cancer cells disseminate and home to bone marrow until primary surgery, usually less than a handful will succeed in establishing manifest metastases months to years later. To identify signals that support survival or outgrowth in patients, we profile rare bone marrow-derived disseminated cancer cells (DCCs) long before manifestation of metastasis and identify IL6/PI3K-signaling as candidate pathway for DCC activation. Surprisingly, and similar to mammary epithelial cells, DCCs lack membranous IL6 receptor expression and mechanistic dissection reveals IL6 trans-signaling to regulate a stem-like state of mammary epithelial cells via gp130. Responsiveness to IL6 trans-signals is found to be niche-dependent as bone marrow stromal and endosteal cells down-regulate gp130 in premalignant mammary epithelial cells as opposed to vascular niche cells. PIK3CA activation renders cells independent from IL6 trans-signaling. Consistent with a bottleneck function of microenvironmental DCC control, we find PIK3CA mutations highly associated with late-stage metastatic cells while being extremely rare in early DCCs. Our data suggest that the initial steps of metastasis formation are often not cancer cell-autonomous, but also depend on microenvironmental signals.

BackgroundAppendectomy is increasingly performed as a ‘short stay’ or ‘ambulatory’ procedure, yet there is no consensus for selection of patients with acute appendicitis for ambulatory surgery (AS). We aimed to compare characteristics and outcomes of complicated and uncomplicated appendectomies performed in ambulatory vs. conventional settings, and to determine factors associated with unexpected re-consultations and re-hospitalizations.MethodsThe authors reviewed a consecutive series of 185 laparoscopic appendectomies. Whenever possible, patients were offered AS, defined as ‘discharge on the same working day.’ Multivariable regressions were performed to determine associations of unexpected re-consultations and re-hospitalizations with surgery type (ambulatory or conventional) and patient characteristics (age, gender, obesity, symptoms, appendicolith, perforations, appendix diameter, serologic results, American Society of Anesthesiologists score, and Saint-Antoine score).ResultsFrom the initial cohort, 117 patients (63.2%) were eligible for AS, of which 8 had peri- or post-operative contraindications. Therefore, 109 patients (58.9%) were operated by AS, with median length of stay 8.5 h (range, 3.3–20.5). Ambulatory cases had a lower incidence of complications (11.9%) than conventional cases (25.0%) (p = 0.029). Uni- and multi-variable regressions revealed that unexpected re-consultations were not significantly associated with any of the pre- or peri-operative variables but that unexpected re-hospitalizations were 4 times more likely for patients with appendicolith (OR, 4.32; p = 0.04).ConclusionsAmbulatory surgery could be considered as a standard procedure for both complicated and uncomplicated acute appendicitis. Appendicolith was found to be an independent risk factor for unexpected re-hospitalization and should therefore trigger closer monitoring.

PurposeFamily and friends play a pivotal role in caring for patients with heart failure (HF); however, evidence of the impact of caregiving is limited. The objectives of this study were to describe the burden of caregiving on informal caregivers of patients with chronic HF in China.Materials and methodsA cross-sectional survey of cardiologists, their patients with HF, and those patients’ caregivers was conducted. Patient record forms were completed by 150 cardiologists for 10 consecutive patients. Caregivers of these patients were invited to complete a questionnaire.ResultsOverall, 458 caregivers completed a questionnaire (mean ± standard deviation age 60.1±10.6 years; 60% female; 77% spouses; 74% retired). Caregivers spent a mean of 24.5 (16.9) hours caregiving per week, and a third reported a reduction in their social activity, time for themselves, or time for family. Caregivers in employment took several days off work in the past 3 months owing to caregiving, sometimes resulting in reduced income. Up to 79% of caregivers reported an impact on their physical or emotional well-being, and 57% reported deterioration in their objective health status. Inconsistencies stemming from differences in the three-level five-dimension EuroQol questionnaire and HF Caregiver Questionnaire were observed for the impact of caregiving on caregivers’ health-related quality of life.ConclusionAssisting patients with HF is associated with caregiver burden. Addressing the needs of caregivers may help to promote their continued support and improve patient outcomes.