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Perceived as neither Asian nor completely African, often also neglected by island studies, Madagascar long remained the preserve of Francophone scholarship, absent from Anglo- American historical accounts of an Indian Ocean world. This paper examines the place of Madagascar in the literature at the intersection between Indian Ocean studies and textile studies to argue for its relevance in island studies. While decades of historical research have struggled to create a space for the island state and have not made its ‘islandness’ relevant, the paper shows that scholarship focused on Malagasy cloth has successfully re-placed the ‘Great Island’ in an Indian Ocean world and the larger global order, also making it easier to integrate it into a field of island studies that evolved to lend more attention to spatial and relational forces.

ABSTRACT: Objective: To present a case of lymphocytic hypophysitis (LH) during pregnancy.Methods: Clinical presentation before and after pregnancy and review of the pertinent literature are presented.Results: A 30-year-old woman, G3P2A0, presented at 30 weeks of gestation with headache, polyuria, and hypernatremia (156 mmol/L). Obstetrical history was significant for gestational diabetes mellitus, without previous infertility or autoimmune disorders. Magnetic resonance imaging of the head revealed an enlarged pituitary gland measuring 16 mm with slight compression of the optic chiasm. A clinical diagnosis of LH was made upon laboratory findings of diabetes insipidus, adrenal insufficiency, and central hypothyroidism. The patient was treated with desmopressin, hydrocortisone, and levothyroxine. There was rapid regression of the pituitary enlargement within 10 days. At 38 weeks, the patient gave birth to a healthy baby girl weighing 3,950 g. Post-delivery, she breastfed normally and continued to experience clinical, biochemical, and radiologic improvement at 1-year postpartum.Conclusion: The differential diagnosis of headache and sudden-onset endocrine dysfunction during pregnancy can be challenging, and rapid recognition and management are essential. LH, a rare autoimmune disease characterized by lymphocytic infiltration of the pituitary gland, is part of the differential diagnosis for headache and hypopituitarism during pregnancy. To our knowledge, very few cases of lymphocytic panhypophysitis have been described during pregnancy or the postpartum period. High clinical suspicion and proper hormone assessment are important to establish accurate diagnosis and treatment. A multidisciplinary approach involving endocrinologists and obstetricians can greatly reduce maternal and fetal morbidity resulting from pituitary dysfunction during pregnancy.Abbreviations: ACTH = adrenocorticotropic hormone DI = diabetes insipidus GDM = gestational diabetes mellitus GH = growth hormone IGF-1 = insulin-like growth factor 1 LH = lymphocytic hypophysitis MRI = magnetic resonance imaging

Abstract In the tumour microenvironment, IL-1α promotes neoangiogenesis, matrix remodelling, tumour proliferation, chemoresistance, and metastases. Highly expressed in human colorectal cancers, IL-1α is associated with poor prognosis. XB2001, a fully human monoclonal antibody neutralizing IL-1α, was evaluated for safety and preliminary efficacy with trifluridine/tipiracil (FTD/TPI) and bevacizumab in metastatic colorectal cancer patients previously treated with oxaliplatin- and irinotecan-based chemotherapies. This single institution, phase 1 study used a 3 + 3 design to assess XB2001 at doses of 250 mg, 500 mg and 1000 mg every 14 days, associated with FTD/TPI 35 mg/m² (days 1–5 and 8-12, every 28 days) (NCT05201352). The Maximum Tolerated Dose of XB2001 + FTD/TPI was then associated in combination with bevacizumab (5 mg/kg, days 1 and 15). Safety, efficacy, pharmacokinetics and pharmacodynamics were assessed. Seventeen patients (median age: 67.4 years) were enroled. No patient exhibited dose-limiting toxicity at any dose. The most common treatment-related adverse events (TRAE) of any grade (G) were diarrhoea (35.3%), nausea (47.1%) and anaemia (35.3%). G3-4 TRAE were neutropenia (17.6%) hypertension and infection (5.9% each). The RP2D (recommended phase 2 dose) of XB2001 was 1000 mg. The disease control rate was 76%, with 23% of patients achieving an objective response, including one complete response. Response and longer progression-free survival were associated with a decrease in serum IL-6 levels during therapy. High intratumoral IL-1α expression at baseline and CD8/PD-L1 infiltration are associated with a better progression-free survival. The combination of XB2001 with FTD/TPI and bevacizumab is feasible and safe, and showed encouraging clinical activity in chemotherapy-resistant mCRC.

Abstract Background Elucidating the intricacies of the sugarcane genome is essential for breeding superior cultivars. This economically important crop originates from hybridizations of highly polyploid Saccharum species. However, the large size (10 Gb), high degree of polyploidy, and aneuploidy of the sugarcane genome pose significant challenges to complete genome sequencing, assembly, and annotation. One successful strategy for identifying candidate genes linked to agronomic traits, particularly those associated with sugar accumulation, leverages synteny and potential collinearity with related species. Results In this study, we explored synteny between sorghum and sugarcane. Genes from a sorghum Brix QTL were used to screen bacterial artificial chromosome (BAC) libraries from two Brazilian sugarcane varieties (IACSP93-3046 and SP80-3280). The entire region was successfully recovered, confirming synteny and collinearity between the species. Manual annotation identified 51 genes in the hybrid varieties that were subsequently confirmed to be present in Saccharum spontaneum. This study employed a multifaceted approach to identify candidate genes for sugar accumulation, including retrieving the genomic region of interest, performing a gene-by-gene analysis, analyzing RNA-seq data for internodes from Saccharum officinarum and S. spontaneum accessions, constructing a coexpression network to examine the expression patterns of genes within the studied region and their neighbors, and finally identifying differentially expressed genes (DEGs). Conclusions This comprehensive approach led to the discovery of three candidate genes potentially involved in sugar accumulation: an ethylene-responsive transcription factor (ERF), an ABA 8’-hydroxylase, and a prolyl oligopeptidase (POP). These findings could be valuable for identifying additional candidate genes for other important agricultural traits and directly targeting candidate genes for further work in molecular breeding.

Abstract Background Borderline Personality Disorder (BPD) is one of the most frequent, severe, mental conditions and is associated with a serious burden of disease. Treatment for patients with BPD involves structured psychotherapy. In addition and in order to improve access to care, psychiatric treatments are available. So far, it remains unclear if brief psychiatric intervention according to Good Psychiatric Management (GPM) produces a reliable effect on a variety of clinical outcomes. The assessment of mechanisms of change contributes to focus the treatment on the essential ingredients of change. The current study aims to demonstrate the emotional processing as a mechanism of change, assessed in an ecologically valid experimental context, of brief GPM. Methods The present two-arm randomized controlled study aims at testing the effects (i.e., reduction in borderline symptoms) and emotional processing as mechanism of change of a brief psychiatric treatment (10 sessions over 4 months), compared with treatment as usual. Participants are N = 76 patients with BPD who are either randomized to a 4 month GPM or a 4 month TAU without any BPD-specific content. All patients undergo assessments of borderline symptoms using ZAN-BPD and experiential enactment for assessment of emotional processing, at intake, 2 months and 4 months (discharge). Results The effect of a brief version of GPM is not different from the effect of TAU on the total score of the ZAN-BPD at 4 month (d = 0.04). At the level of the secondary effects, GPM is more effective in reducing relationship problems on the ZAN-BPD sub-scale (F(1, 61) = 5.53; p = .022, d = 0.52), and in reducing impulsivity and social problems, and it increases treatment retention. Change in emotional processing between intake and month 2 mediates the reduction on the ZAN-BPD subscale relationship problems assessed between months 2 and 4, in an ecologically valid experimental context. Conclusions Overall, brief GPM is not different from TAU in terms of reduction in borderline symptoms, but it may produce reduction in relationship problems between months 2 and 4 into the brief intervention. Change in emotional processing in an experimental context may function as mechanism of change of brief GPM. This study is in line with the top priority of establishing efficacy of brief interventions for BPD and proposes an evidence-based explanation for efficacy. These results should help disseminate brief psychiatric treatments for BPD, which contribute to reduce the societal burden related with BPD. Trial registration Clinical Trials NCT03717818 (date of registration of Abstract October 24th, 2018). Protocol number 2 from February 9th, 2018.

Aim: Immune checkpoint inhibitors improved the survival of advanced non-small cell lung cancer. However, only 20% of patients respond to these treatments and the search for predictive biomarkers of response is still topical. The objective of this work is to analyze the anti-PD-1 monotherapy benefit based on genetic alterations diagnosed by next generation sequencing (NGS), in advanced non-small cell lung cancer. Methods: Patients with advanced non-small cell lung cancer treated with immunotherapy were retrospectively included in this monocentric study. Clinical data, immunohistochemical expression of PD-L1 and molecular data, with a 22-genes NGS panel, were collected. Results: 107 patients were included. The median age was 65 years [59; 73], 70 were men (65%), 96 had adenocarcinoma (90%), 33 were receiving a first line (31%). 54 patients had KRAS mutation (50%) and 56 had TP53 mutation (52%). The remaining mutations were present in fewer than 10 patients. There was no statistically significant differences in median of progression-free or overall survival based on KRAS-only, TP53-only or KRAS-TP53 mutations co-mutated compared to double wild-type patients (P = 0.46 and P = 0.72 respectively). Conclusions: The search for a predictive composite biomarker remains a major issue in the coming years.

Abstract Glioblastoma multiforme (GBM) is the most common adult primary brain tumor. The standard of care involves maximal surgery followed by radiotherapy and concomitant chemotherapy with temozolomide (TMZ), in addition to adjuvant TMZ. However, the recurrence rate of GBM within 1–2 years post-diagnosis is still elevated and has been attributed to the accumulation of multiple factors including the heterogeneity of GBM, genomic instability, angiogenesis, and chronic tumor hypoxia. Tumor hypoxia activates downstream signaling pathways involved in the adaptation of GBM to the newly oxygen-deprived environment, thereby contributing to the resistance and recurrence phenomena, despite the multimodal therapeutic approach used to eradicate the tumor. Therefore, in this review, we will focus on the development and implication of chronic or limited-diffusion hypoxia in tumor persistence through genetic and epigenetic modifications. Then, we will detail the hypoxia-induced activation of vital biological pathways and mechanisms that contribute to GBM resistance. Finally, we will discuss a proteomics-based approach to encourage the implication of personalized GBM treatments based on a hypoxia signature.

Abstract Background There is growing evidence that spending time with or in nature can be beneficial for health and wellbeing. Emerging evidence suggests potential benefits for staff and service users in healthcare settings, yet little is known about how to put Nature-based approaches (NBAs) into practice within the Child and Adolescent Mental Health Services (CAMHS) setting. The CAMHS Goes Wild project in Southwest England aimed to explore the implementation of NBAs within CAMHS, examining staff attitudes and understanding to identify potential benefits and challenges through a mixed methods study. Methods The study involved three phases of data collection: an online survey with two waves, the first wave prior to the training, and the second four months post-training, and semi-structured interviews. Data collection was designed to fit around NatureWell training, attended by sixty-four CAMHS staff, which took place alongside the study. All participants were sampled from one NHS Trust and the study was open to both those who had attended the NatureWell training and those who had not. Data were synthesised to produce an understanding of staff attitudes towards NBAs and perceived barriers and facilitators to the implementation of this approach. Results Ninety-seven staff responded to the wave 1 survey and 57 responded to the wave 2 survey. Fourteen staff members were interviewed. Data synthesis generated three themes: Tension between the culture of CAMHS and NBAs (Theme 1) and the need for buy-in and governance support (Theme 2). Theme three described the potential benefits of NBAs for staff and service users in CAMHS and is presented in a separate paper. The first two themes are presented in this paper. Conclusions The implementation of NBAs in mental health service settings for CYP presents both significant challenges and opportunities. Our findings suggest multiple barriers to implementation, often in the form of organisational or cultural factors, such as the risk averse nature of the service. Our work also elucidates several potential facilitators which may address or mitigate some of these barriers. These potential enablers, such as harnessing the role of firsthand experience, warrant further exploration in the implementation of NBAs in CAMHS.

Abstract Domestication – the artificial selection of wild species to obtain variants with traits of human interest – was integral to the rise of complex societies. The oversupply of food was probably associated with the formalization of food preservation strategies through microbial fermentation. While considerable literature exists on the antiquity of fermented food, only few eukaryotic microbes have been studied so far for signs of domestication, less is known for bacteria. Here, we tested if cheese starter cultures harbour typical hallmarks of domestication by characterising over 100 community samples and over 100 individual strains isolated from historical and modern traditional Swiss cheese starter cultures. We find that cheese starter cultures have low genetic diversity both at the species and strain-level and maintained stable phenotypic traits. Molecular clock dating further suggests that the evolutionary origin of the bacteria approximately coincided with the first archaeological records of cheese making. Finally, we find evidence for ongoing genome decay and pseudogenization via transposon insertion related to a reduction of their niche breadth. Future work documenting the prevalence of these hallmarks across diverse fermented food systems and geographic regions will be key to unveiling the joint history of humanity with fermented food microbes.

Abstract Stressed bacteria can enter a dormant viable but non-culturable (VBNC) state. VBNC pathogens pose an increased health risk as they are undetectable by growth-based techniques and can wake up back into a virulent state. Although widespread in bacteria, the mechanisms governing this phenotypic switch remain elusive. Here, we investigate the VBNC state transition in the human pathogen Listeria monocytogenes. We show that bacteria starved in mineral water become VBNC by converting into osmotically stable cell wall-deficient coccoid forms, a phenomenon that occurs in other Listeria species. We reveal the bacterial stress response regulator SigB and the autolysin NamA as major actors of VBNC state transition. We lastly show that VBNC Listeria revert to a walled and virulent state after passage in chicken embryos. Our study provides more detail on the VBNC state transition mechanisms, revealing wall-free bacteria naturally arising in aquatic environments as a potential survival strategy in hypoosmotic and oligotrophic conditions.

Abstract Laser assisted in situ keratomileusis (LASIK) surgery is the leading and most performed refractive surgery nowadays. A possible complication of LASIK surgery is infectious keratitis which can lead to disastrous corneal damage and result in permanent loss of vision. LASIK procedures have become increasingly accessible, and the demand for refractive surgery has risen among patients, challenging the medical field to improve the prevention of post-operative infections. Nevertheless, a wide range of pathogens have been described as responsible for post-LASIK keratitis. However, non-tuberculous mycobacterial keratitis remains an infrequent occurrence and is poorly described in the literature. To the best of our knowledge, this is the first ever reported case of post-LASIK keratitis caused by Mycobacterium wolinskyi. We describe the clinical and microbial characteristics, leading to its challenging treatment choice.

Abstract Background The present analysis aimed to assess the mediating role of psychosocial and behavioural factors in socio-economic inequalities in health-related quality of life (HRQoL) among children and adolescents. Methods Cross-sectional data was drawn from the randomly selected SEROCoV-KIDS cohort study in Geneva, Switzerland. Associations of socio-economic conditions (parents’ highest education, household financial situation) with HRQoL, psychosocial (parent–child relationship, school difficulties, friends, extracurricular activities) and behavioural factors (screen time, physical activity, green spaces time, sleep duration), along with associations of psychosocial and behavioural factors with HRQoL, were evaluated with generalized estimating equations. Counterfactual mediation analyses were conducted to test pathways linking socio-economic conditions to HRQoL. Results Of 965 children and 816 adolescents, those with disadvantaged financial circumstances were more likely to have a poor HRQoL (adjusted Odds Ratio [aOR]: 3.80; 95% confidence interval [CI]: 1.96–7.36 and aOR: 3.66; 95%CI: 2.06–6.52, respectively). Psychosocial characteristics mediated 25% (95%CI: 5–70%) and 40% (95%CI: 18–63%) of financial disparities in HRQoL among children and adolescents, respectively. Health behaviours were weakly patterned by socio-economic conditions and did not contribute to financial differences in HRQoL. Conclusions These findings provide empirical evidence for mechanisms explaining socio-economic disparities in child HRQoL and could inform interventions aimed to tackle health inequalities.

Respiratory infections with respiratory syncytial virus (RSV) account for an important part of hospital admissions for acute respiratory infections. Nirsevimab has been developed to reduce the hospital burden of RSV infections. Compared with the product previously used, it has a stronger binding capacity to RSV F protein and a high affinity for FcRn (neonatal receptor for the Fc fragment of IgG), which extends its lifespan. Nirsevimab has been shown to be highly effective in reducing hospitalization rates of RSV infections but a large or unknown number of treated subjects have been excluded in clinical and post-marketing studies. However, analysis of these studies cannot exclude that, in rare cases, nirsevimab facilitates and worsens RSV infection (or other respiratory infections). This could be attributable to antibody-dependent enhancement (ADE) which has been observed with RSV F protein antibodies in inactivated vaccine trials. This risk has been incompletely assessed in pre-clinical and clinical trials (incomplete exploration of nirsevimab effector functions and pharmacokinetics). ADE by disruption of the immune system (not studied and due to FcRn binding) could explain why there is no reduction in all-cause hospital admissions in treated age groups. Given the high price of nirsevimab, the cost-effectiveness of mass immunization campaigns may therefore be debated from an economic as well as a scientific point of view.

Abstract Background Microsatellite instability (MSI) due to mismatch repair deficiency (dMMR) is common in colorectal cancer (CRC). These cancers are associated with somatic coding events, but the noncoding pathophysiological impact of this genomic instability is yet poorly understood. Here, we perform an analysis of coding and noncoding MSI events at the different steps of colorectal tumorigenesis using whole exome sequencing and search for associated splicing events via RNA sequencing at the bulk-tumor and single-cell levels. Results Our results demonstrate that MSI leads to hundreds of noncoding DNA mutations, notably at polypyrimidine U2AF RNA-binding sites which are endowed with cis-activity in splicing, while higher frequency of exon skipping events are observed in the mRNAs of MSI compared to non-MSI CRC. At the DNA level, these noncoding MSI mutations occur very early prior to cell transformation in the dMMR colonic crypt, accounting for only a fraction of the exon skipping in MSI CRC. At the RNA level, the aberrant exon skipping signature is likely to impair colonic cell differentiation in MSI CRC affecting the expression of alternative exons encoding protein isoforms governing cell fate, while also targeting constitutive exons, making dMMR cells immunogenic in early stage before the onset of coding mutations. This signature is characterized by its similarity to the oncogenic U2AF1-S34F splicing mutation observed in several other non-MSI cancer. Conclusions Overall, these findings provide evidence that a very early RNA splicing signature partly driven by MSI impairs cell differentiation and promotes MSI CRC initiation, far before coding mutations which accumulate later during MSI tumorigenesis.

Abstract The demographical history of France remains largely understudied despite its central role toward understanding modern population structure across Western Europe. Here, by exploring publicly available Europe-wide genotype datasets together with the genomes of 3234 present-day and six newly sequenced medieval individuals from Northern France, we found extensive fine-scale population structure across Brittany and the downstream Loire basin and increased population differentiation between the northern and southern sides of the river Loire, associated with higher proportions of steppe vs. Neolithic-related ancestry. We also found increased allele sharing between individuals from Western Brittany and those associated with the Bell Beaker complex. Our results emphasise the need for investigating local populations to better understand the distribution of rare (putatively deleterious) variants across space and the importance of common genetic legacy in understanding the sharing of disease-related alleles between Brittany and people from western Britain and Ireland.

Introduction Alcohol use disorder (AUD) is a massive burden for the individual, relatives and society. Despite this, the treatment gap is wide compared with other mental health disorders. Treatment options are sparse, with only three Food and Drug Administration (FDA)-approved pharmacotherapies. Glucagon-like peptide-1 (GLP-1) receptor agonists have shown promising effects in reducing alcohol consumption in preclinical experiments, and clinical trials are in high demand to investigate these potentially beneficial effects in patients diagnosed with AUD.Methods and analysis The effects of the once-weekly GLP-1 receptor agonist semaglutide will be investigated in a 26-week, randomised, placebo-controlled, double-blinded clinical trial. 108 patients diagnosed with AUD and comorbid obesity (body mass index (BMI)≥30 kg/m2)) will be randomised to treatment with either semaglutide or placebo in combination with cognitive behavioural therapy. A subgroup of the patients will have structural, functional and neurochemical brain imaging performed at baseline and after 26 weeks of treatment. The primary endpoint is the reduction in heavy drinking days, defined as days with excess consumption of 48/60 g of alcohol per day (women and men, respectively). Secondary endpoints include changes from baseline to week 26 in alcohol consumption, smoking status, quality of life, fibrosis-4 score, plasma concentration of phosphatidylethanol, brain gamma-aminobutyric acid (GABA) levels, alcohol cue reactivity, functional connectivity and white matter tract integrity.Status Recruitment started in June 2023.Ethics and dissemination The study is approved by the Ethics Committee of the Capital Region of Denmark, the Danish Board of Health and the Danish Data Protection Agency. All patients will sign the written consent form before being included in the trial. Results will be disseminated through peer-reviewed publications and conference presentations. After the results are published, all de-identified data will be available in the Mendeley database.Trial registration number NCT05895643.

Objectives This study aims (1) to assess the prevalence of severe fatigue among the general population of Geneva, 2 years into the COVID-19 pandemic and (2) to identify pandemic and non-pandemic factors associated with severe fatigue.Design Cross-sectional population-based survey conducted in Spring 2022.Setting General adult population of Geneva, Switzerland.Participants 6870 adult participants, randomly selected from the general population, included in the Specchio-COVID-19 cohort study, were invited to answer an online health survey.Outcome and cofactor measure Prevalence of severe fatigue was measured by the Chalder Fatigue Questionnaire with a cut-off score≥4 out of 11. We assessed prevalence ratios of severe fatigue considering sociodemographic factors, health and behavioural characteristics (body mass index, depression, recent diagnosis of chronic disease or allergy, acute health event, smoking status, physical activity and sleep quality) and recent self-reported COVID-19 infections.Results A total of 4040 individuals participated (participation rate 59%, 58% were women, mean age 53.2 (SD=14.1 years)). Overall prevalence of severe fatigue was 30.7% (95% CI=29.2%–32.1%). After adjusting for age, sex, educational level and pre-existing comorbidities, the following characteristics were associated with severe fatigue: individuals aged 18–24 years (adjusted prevalence ratio (aPR)=1.39 (1.10–1.76)) and 25–34 years (aPR=1.23 (1.05–1.45)), female sex (aPR=1.28 (1.16–1.41)), depression (aPR=2.78 (2.56–3.01)), occurrence of health events unrelated to COVID-19 (aPR=1.51 (1.38–1.65)) and self-reported COVID-19 infection in the past 12 months (aPR=1.41 (1.28–1.56)). After further adjustment for depression, previous associations were maintained except for young age.Conclusions About one-third of the adult general population of Geneva experienced severe fatigue, 2 years into the COVID-19 pandemic. Heightened fatigue among young adults is partly explained by depressive symptoms. Recent COVID-19 infection is substantially associated with severe fatigue, regardless of infection severity or co-occurrence of depressive disorder.Trial registration number CCER project ID 2020-00881.