Search

Abstract The spermosphere, a dynamic microenvironment surrounding germinating seeds, is shaped by the complex interactions between natural compounds exuded by seeds and seed-associated microbial communities. While peptides exuded by plants are known to influence microbiota diversity, little is known about those specifically exuded by seeds. In this study, we characterised the peptidome profile of the spermosphere for the first time using seeds from eight genotypes of common bean (Phaseolus vulgaris) grown in two contrasting production regions. An untargeted LC-MS/MS peptidomic analysis revealed 3,258 peptides derived from 414 precursor proteins of common bean in the spermosphere. This comprehensive peptidomic dataset provides valuable insights into the characteristics of peptides exuded by common bean seeds in the spermosphere. It can be used to identify peptides with potential antimicrobial or other biological activities, advancing our understanding of the functional roles of seed-exuded peptides in the spermosphere.

Abstract Solanum aethiopicum L. and Solanum melongena L. are endemic plants whose fruits are used in the composition of cultural dishes in West Cameroon including Yellow, Black, Eggplant, Nkui and Okra sauces. This work aims to conduct an ethnonutritional study based on the knowledge and consumption of these dishes. Surveys were carried out including 480 persons of the district of Galim (Kieneghang I and Mbezaté) in the Bamboutos division in West Cameroon and the results revealed that the vernacular and common names for Solanum aethiopicum L. and Solanum melongena L. are respectively “Shusshui” and “sweet egglant”; “Nzuinzuiè” and “bitter eggplant”. These fruits are rounded and spindle in shape. The fruits of Solanum aethiopicum L. exist in green, yellow and red colors with a mild flavor, while those of Solanum melongena L. are red and bitter. These fruits are preserved by sun-drying, smoking, and parboiled before drying. Their cultivation is traditional with a duration of 3–7 months using organic and chemical fertilizers. The age group 41–50 years had a good knowledge of fruits while the age group over 60 years had a better consumption frequency of eggplant-dishes. In addition, these fruits have important cultural values during traditional ceremonies at births, weddings, funerals, symbolisms such as acceptance, reconciliation, hospitality, consideration, and valorisation. These populations had knowledge for the prevention and or treatment of diabetes (6.66%), high blood pressure (25%), obesity (13.54%), cancers (1.66%) and mouth ulcers (2.70%). The valorization of these fruits could constitute a means of preserving cultural heritage.

Abstract Background The frequency of health-related information seeking on the internet and social media platforms has increased remarkably. Thus, the ability to understand and select accurate health-related information online, known as EHealth literacy, is crucial for the population. Therefore, this study aimed to evaluate how eHealth literacy influences the critical analysis of oral health-related information obtained from the Internet and its influence on oral health-related behaviors. Methods A cross-sectional online study was conducted with 418 Brazilian adults who responded to the eHEALS questionnaire, with questions regarding the influence of online information on oral health decisions. Socioeconomic and demographic characteristics were also collected. Results The mean eHEALS score was 27.85 (± 8.13), with a range spanning from 8 to 40 points. Participants with higher eHEALS scores reported using social media platforms to seek for dentists and to acque information about symptoms, diagnoses, and treatments. Furthermore, this group tended not to disregard professional health recommendations based on Internet information and abstained from utilizing products promoted by digital influencers. In multivariate models, increased eHEALS scores were associated with reduced consumption of products endorsed by digital influencers. Conclusions The findings from this study suggest that individuals with higher scores on the eHealth literacy questionnaire often conduct research on their health status and seek for health care providers on the Internet. Moreover, these individuals were less likely to be influenced by digital influencers.

Summary: Background: In industrialized countries, the incidence of inflammatory bowel disease (IBD) appears stabilized. This study examined the incidence and phenotype of IBD in Northern France over a 30-year period. Methods: Including all IBD patients recorded in the EPIMAD population-based registry from 1988 to 2017 in Northern France, we described the incidence and clinical presentation of IBD according to age, sex and time. Findings: A total of 22,879 incident IBD cases were documented (59% (n = 13,445) of Crohn’s disease (CD), 38% (n = 8803) of ulcerative colitis (UC), 3% (n = 631) of IBD unclassified (IBDU)). Over the study period, incidence of IBD, CD and UC was 12.7, 7.2 and 5.1 per 105 person-years, respectively. The incidence of CD increased from 5.1/105 in 1988–1990 to 7.9/105 in 2015–2017 (annual percent change (APC): +1.9%, p

ABSTRACT Objective: To describe the clinical and sociodemographic profile and associate them with the quality of life of adolescents with type 1 diabetes mellitus being followed up in a public hospital in an inner city of the state of São Paulo. Method: Quantitative, cross-sectional, and analytical study, performed with 80 dyads. Data were collected through a clinical/sociodemographic form and a Quality of Life Instrument. For analysis, descriptive statistics were used, and Pearson's Chi-square and Fisher's Exact tests were applied to assess the association between quality of life and clinical/sociodemographic variables. Results: Out of the total participants, the ones who scored high quality of life were mostly, female (52.5%), in the age group 15 to 17 years old (56.3%), 51.3% self-identified as white, and 40.1% were attending high school. In the preoccupation domain, a significant association was found to the time since diagnosis (p=0.035), demonstrating that young adolescents with a longer time of diagnosis had a worse quality of life. Conclusion: The majority of adolescents in this study (51.3%) had been living with diabetes for 10 or more years. It was identified that the duration of the diagnosis has the potential to interfere with the quality of life of these young individuals.

Traditionally, coronary angiography was restricted to visual estimation of contrast-filled lumen in coronary obstructive diseases. Over the previous decades, considerable development has been made in quantitatively analyzing coronary angiography, significantly improving its accuracy and reproducibility. Notably, the integration of artificial intelligence (AI) and machine learning into quantitative coronary angiography (QCA) holds promise for further enhancing diagnostic accuracy and predictive capabilities. In addition, non-invasive fractional flow reserve (FFR) indices, including computed tomography-FFR, have emerged as valuable tools, offering precise physiological assessment of coronary artery disease without the need for invasive procedures. These innovations allow for a more comprehensive evaluation of disease severity and aid in guiding revascularization decisions. This review traces the development of QCA technologies over the years, highlighting key milestones and current advancements. It also explores prospects that could revolutionize the field, such as AI integration and improved imaging techniques. By addressing both historical context and future directions, the article underscores the ongoing evolution of QCA and its critical role in the accurate assessment and management of coronary artery diseases. Through continuous innovation, QCA is poised to remain at the forefront of cardiovascular diagnostics, offering clinicians invaluable tools for improving patient care.

ABSTRACT Objective: To apprehend the family's perception of the care provided by home care services to children and adolescents with special health needs. Method: Qualitative, exploratory-descriptive study, carried out with 15 family members of children and adolescents with special health needs served by Home Care Services in seven municipalities in Paraíba, in 2021, selected from nine municipalities identified by previous studies. Data were collected using semi-structured interviews carried out remotely through telephone calls. The empirical material was subjected to Inductive Thematic Analysis and interpreted in light of the concept of health vulnerability. Results: The Home Care Services facilitate minimize the health vulnerabilities of these children and adolescents and their families as they facilitate access to the actions and services of the Health Care Network, provide humanized care focused on promoting health and strengthening bonds, as well as how, they facilitate family decision-making at home regarding users' health needs. Final considerations: The actions of these services permeate family daily life, enabling the expansion of care practices for family members/caregivers considering their limitations and improving the coordination of Health Care Networks to guarantee comprehensive care.

ABSTRACT Molecular methods are routinely used to estimate the effective size of populations (Ne). However, underlying model assumptions are frequently violated to an unknown extent. Although simulations can detect sources of bias and help to adjust sampling strategies and analyses methods, additional information from empirical data can also be used to calibrate methods and improve molecular Ne estimation methods. Here, we take advantage of long‐term genetic and ecological monitoring data of the grey wolf (Canis lupus) in Germany, and detailed population genetic studies in Poland, Spain and Portugal to improve Ne estimation strategies in this species, and species with similar life history traits. We first calculated Ne from average lifetime reproductive success and detailed census data from the German population, which served as a baseline to compare to molecular estimates based on linkage disequilibrium and sibship frequency. This yielded a robust Ne/Nc estimation that we used to calibrate molecular estimates of German, Polish and Iberian wolf populations. The linkage disequilibrium method was strongly influenced by spatial genetic structure, much more than the sibship frequency method. When Ne was estimated in local neighbourhoods, both methods yielded comparable results. Estimates of the metapopulation effective size seemed to correspond generally well with the sum of the estimates of local neighbourhoods. Overall, we found that the number of packs is a good proxy of the effective population size. Using this as a rule of thumb, we evaluated for all European wolf populations the Ne 500 indicator and concluded that half of the European wolf populations do not yet fulfil this criterion.

Introduction Tetraplegia causes extensive sensorimotor deficits affecting activity, participation and quality of life. People with C6-C7 tetraplegia can learn to grasp objects by performing wrist extension movement (ie, tenodesis grasp), and motor imagery (MI) added to rehabilitation significantly improved tenodesis grasp. We hypothesise that this improvement can be further boosted by adding neurofeedback during MI. Thus, we design a randomised controlled trial investigating the effect of MI training on grasping ability in people with C6-C7 tetraplegia.Methods and analysis We will perform a bicentric, assessor-blinded, randomised controlled study. During rehabilitation, 21 inpatients with C6-C7 tetraplegia will be allocated to MI with neurofeedback (MI training with graphical display on a computer screen based on mu (8–13 Hz) and beta (18–25 Hz) frequency rhythms measured with 32-channel electroencephalography), MI alone (only MI training) and control (watching movies and visualisation of geometric shapes). All participants will receive three 45-min training sessions per week for 5 weeks.The primary outcome measure will be wrist extension angle immediately after the intervention during tenodesis grasp measured with a 3D motion analysis system (VICON). Secondary outcomes will include a range of measures: kinematic, grip strength, upper limb range of motion, upper limb strength (manual muscle test and hand-held dynamometer measure), dexterity (box and block test, 9-hole peg test, Jebsen test, capabilities of upper extremity questionnaire), quality of life (WHOQOL-Bref), daily life autonomy (Quadriplegic Index of Function), MI capacity and brain reorganisation (magnetoencephalography only available in Lyon, n=15). We will measure all outcomes five times: during weeks 1, 3 and 5 (baseline), week 11 (immediately after the intervention end) and week 18 (8 weeks after the intervention end).Ethics and dissemination Ethical approval was granted on 29 September 2017 (CPP Nord-Ouest-IV 17/25, N°2017-A00990-53). Dissemination will occur via presentation of results in scientific meetings and publication in peer-reviewed academic journals.Trial registration number NCT03190863 (ClinicalTrials.gov).

Abstract Background Viperin, also known as radical S-adenosyl-methionine domain containing protein 2 (RSAD2), is an interferon-inducible protein that is involved in the innate immune response against a wide array of viruses. In mammals, Viperin exerts its antiviral function through enzymatic conversion of cytidine triphosphate (CTP) into its antiviral analog ddhCTP as well as through interactions with host proteins involved in innate immune signaling and in metabolic pathways exploited by viruses during their life cycle. However, how Viperin modulates the antiviral response in fish remains largely unknown. Results For this purpose, we developed a fathead minnow (Pimephales promelas) clonal cell line in which the unique viperin gene has been knocked out by CRISPR/Cas9 genome-editing. In order to decipher the contribution of fish Viperin to the antiviral response and its regulatory role beyond the scope of the innate immune response, we performed a comparative RNA-seq analysis of viperin −/− and wildtype cell lines upon stimulation with recombinant fathead minnow type I interferon. Conclusions Our results revealed that Viperin does not exert positive feedback on the canonical type I IFN but acts as a negative regulator of the inflammatory response by downregulating specific pro-inflammatory genes and upregulating repressors of the NF-κB pathway. It also appeared to play a role in regulating metabolic processes, including one carbon metabolism, bone formation, extracellular matrix organization and cell adhesion.

Abstract In honey bees, circulation of blood (hemolymph) is driven by the peristaltic contraction of the heart vessel located in the dorsal part of the abdomen. Chlorantraniliprole (CHL) is an insecticide of the anthranilic diamide class which main mode of action is to alter the function of intracellular Ca2+ release channels (known as RyRs, for ryanodine receptors). In the honey bee, it was recently found to be more toxic when applied on the dorsal part of the abdomen, suggesting a direct cardiotoxicity. In the present study, a short-term exposure of semi-isolated bee hearts to CHL (0.1–10 µM) induces alterations of cardiac contraction. These alterations range from a slow-down of systole and diastole kinetics, to bradycardia and cardiac arrest. The bees heart wall is made of a single layer of semi-circular cardiomyocytes arranged concentrically all along the long axis of tube lumen. Since the heart tube is suspended to the cuticle through long tubular muscles fibers (so-called alary muscle cells), the CHL effects in ex-vivo heart preparations could result from the modulation of RyRs present in these skeletal muscle fibers as well as cardiomyocytes RyRs themselves. In order to specifically assess effects of CHL on cardiomyocytes, for the first time, intact heart cells were enzymatically dissociated from bees. Exposure of cardiomyocytes to CHL induces an increase in cytoplasmic calcium, cell contraction at the highest concentrations and depletion of intracellular stores. Electrophysiological properties of isolated cardiomyocytes were described, with a focus on voltage-gated Ca2+ channels responsible for the cardiac action potentials depolarization phase. Two types of Ca2+ currents were measured under voltage-clamp. Exposure to CHL was accompanied by a decrease in voltage-activated Ca2+ currents densities. Altogether, these results show that chlorantraniliprole can cause cardiac defects in honey bees.

Calcium is a ubiquitous messenger that regulates a wide range of cellular functions, but its involvement in the pathophysiology of acute myeloid leukemia (AML) is not widely investigated. Here, we identified, from an analysis of The Cancer Genome Atlas and genotype‐tissue expression databases, stromal interaction molecule 2 (STIM2) as being highly expressed in AML with monocytic differentiation and negatively correlated with overall survival. This was confirmed on a validation cohort of 407 AML patients. We then investigated the role of STIM2 in cell proliferation, differentiation, and survival in two leukemic cell lines with monocytic potential and in normal hematopoietic stem cells. STIM2 expression increased at the RNA and protein levels upon monocyte differentiation. Phenotypically, STIM2 knockdown drastically inhibited cell proliferation and induced genomic stress with DNA double‐strand breaks, as shown by increased levels of phosphorylate histone H2AXγ (p‐H2AXγ), followed by activation of the cellular tumor antigen p53 pathway, decreased expression of cell cycle regulators such as cyclin‐dependent kinase 1 (CDK1)–cyclin B1 and M‐phase inducer phosphatase 3 (CDC25c), and a decreased apoptosis threshold with a low antiapoptotic/proapoptotic protein ratio. Our study reports STIM2 as a new actor regulating genomic stability and p53 response in terms of cell cycle and apoptosis of human normal and malignant monocytic cells.

Abstract By incompletely understood mechanisms, type 2 (T2) inflammation present in the airways of severe asthmatics drives the formation of pathologic mucus which leads to airway mucus plugging. Here we investigate the molecular role and clinical significance of intelectin-1 (ITLN-1) in the development of pathologic airway mucus in asthma. Through analyses of human airway epithelial cells we find that ITLN1 gene expression is highly induced by interleukin-13 (IL-13) in a subset of metaplastic MUC5AC+ mucus secretory cells, and that ITLN-1 protein is a secreted component of IL-13-induced mucus. Additionally, we find ITLN-1 protein binds the C-terminus of the MUC5AC mucin and that its deletion in airway epithelial cells partially reverses IL-13-induced mucostasis. Through analysis of nasal airway epithelial brushings, we find that ITLN1 is highly expressed in T2-high asthmatics, when compared to T2-low children. Furthermore, we demonstrate that both ITLN-1 gene expression and protein levels are significantly reduced by a common genetic variant that is associated with protection from the formation of mucus plugs in T2-high asthma. This work identifies an important biomarker and targetable pathways for the treatment of mucus obstruction in asthma.

This study investigated the effect of some herbal extracts, such as licorice root, white mulberry leaf, green tea leaf, and grape seed, with a combination of bacterial nanocellulose and some bioactive materials, such as ascorbic acid, niacinamide, hexylresorcinol, and alpha-arbutin, on treatment of hyperpigmentation. The effect of the prepared emulsions on hyperpigmentation was revealed by analyzing their tyrosinase inhibition properties, their ability to stop melanin production, or their properties of whitening the brown spot on the skin. In addition to the physicochemical properties of the 5 different emulsions obtained, tyrosinase, collagenase, and elastase enzyme activities, antioxidant properties, cytotoxicity, and microbiological analyzes were performed by cell-culture modelling. Finally, a dermocosmetic facial serum was designed that is compatible with skin pH, is homogeneously mixed, has good spreading properties, does not cause any microbiological growth, does not inhibit elastase activity while stimulating collagenase activity, reduces melanin production by inhibiting the tyrosinase enzyme, and does not have any toxic effects.

This study investigated the effect of some herbal extracts, such as licorice root, white mulberry leaf, green tea leaf, and grape seed, with a combination of bacterial nanocellulose and some bioactive materials, such as ascorbic acid, niacinamide, hexylresorcinol, and alpha-arbutin, on treatment of hyperpigmentation. The effect of the prepared emulsions on hyperpigmentation was revealed by analyzing their tyrosinase inhibition properties, their ability to stop melanin production, or their properties of whitening the brown spot on the skin. In addition to the physicochemical properties of the 5 different emulsions obtained, tyrosinase, collagenase, and elastase enzyme activities, antioxidant properties, cytotoxicity, and microbiological analyzes were performed by cell-culture modelling. Finally, a dermocosmetic facial serum was designed that is compatible with skin pH, is homogeneously mixed, has good spreading properties, does not cause any microbiological growth, does not inhibit elastase activity while stimulating collagenase activity, reduces melanin production by inhibiting the tyrosinase enzyme, and does not have any toxic effects.

Abstract Large carnivores such as wolves (Canis lupus) at times disperse distances of several hundred kilometers, which may enable gene flow over vast distances. Such long‐distance dispersal events, however, often remain undetected, and documenting long‐distance dispersers and their movements typically depend on strong transboundary collaborations. Here, we report the dispersal of a wolf (MSV0FF) from the Alpine region of northern Slovenia to Bavaria in southern Germany, a straight‐line distance of around 300 km. The disperser originated in a pack with a genetically diverse breeding pair, where the father exhibited ancestry from the Dinaric and Italian Alpine populations. Genetic analysis of the mother indicated that she was an immigrant from a divergent population further south in the Dinaric‐Balkan region. Such a varied ancestry augments the probability of immigrants being genetically misclassified as wolf‐dog hybrids in their area of arrival, which increases the risk of unfavorable management decisions toward individuals that would be genetically highly valuable for the recipient population. Wolf MSV0FF therefore demonstrates the benefits of international collaborative monitoring networks and the value of sharing samples and analytical approaches for the monitoring of wide‐ranging species.

ABSTRACT The aim of this study was to evaluate the effects of diphenyl diselenide (PhSe) supplementation during the transition period on the metabolism, immunity, oxidative status, and milk production of postpartum dairy cows. Twenty-seven Holstein females were divided into groups: (PhSe) (DDG), which received 3 μmol/kg of (PhSe)2 in 4 mL of dimethyl sulfoxide (DMSO) subcutaneously, DMSO (DMSOG), and NaCl (NACLG) which received 4 mL of DMSO and 0.9% NaCl. Evaluation of body condition score (BCS), weighing and administrations were performed at 42, 28, and 14 days prepartum, and on the day of calving (0). On days 0, 7, 14, 21, and 35 postpartum, BCS was evaluated, and blood were collected. Colostrum was obtained from the first postpartum milking. Production was measured, and milk was collected on days 7, 14, 21, and 35 postpartum. DDG showed higher values of total protein (TP) and globulins (GLOB) 7 days postpartum and increase from day 0 to days 21 and 35. DDG immunoglobulin G (IgG) was higher on days 21 and 35, and increased between days 7 and 21. In postpartum TP, GLOB and IgG are physiologically reduced, therefore, the results indicate that supplementation of transition females with (PhSe) stimulated postpartum humoral immunity.

Le constat de la traversée analytique de la lettre, dont Lacan s’est saisi pour mettre en lumière les modalités de manifestation de l’inconscient, incite à nous pencher sur ses apports, plus spécifiquement dans le champ d’une clinique à l’épreuve du trauma et du transfert. C’est à partir de deux experiences cliniques, celle avec Fatah, enfant mutique, et M. U., souffrant d’une névrose dite “traumatique”, que nous aborderons les modalités d’évolution d’une lettre qui, via le transfert, tente de retrouver son inscription symbolique. Nous verrons que de ces rencontres advient la possibilité d’une réarticulation de la lettre, cette dernière fonctionnant comme mise en bouche d’une parole à advenir, une trace qui engage la dimension du réel et du corps organique, dans leur dialogue impossible et à jamais inachevé avec le langage.

The mechanism underlying ischaemic heart disease (IHD) has been primarily attributed to obstructive coronary artery disease (CAD). However, non-obstructive coronary arteries are identified in >50% of patients undergoing elective coronary angiography, recently leading to growing interest in the investigation and management of angina/ischaemia with non-obstructive coronary arteries (ANOCA/INOCA). INOCA is an umbrella term encompassing a multiple spectrum of possible pathogenetic entities, including coronary vasomotor disorders which consist of two major endotypes: coronary microvascular dysfunction (CMD) and vasospastic angina. Both conditions can coexist and be associated with concomitant obstructive CAD. Particularly, CMD refers to myocardial ischaemia due to reduced vasodilatory capacity of coronary microcirculation secondary to structural remodelling or impaired resting microvascular tone (functional) or a combination of both. CMD is not a benign condition and is more prevalent in women presenting with chronic coronary syndrome compared to men. In this setting, an impaired coronary flow reserve has been associated with increased risk of major adverse cardiovascular events. ANOCA/INOCA patients also experience impaired quality of life and associated increased healthcare costs. Therefore, research in this scenario has led to better definition, classification, and prognostic stratification based on the underlying pathophysiological mechanisms. The development and validation of non-invasive imaging modalities, invasive coronary vasomotor function testing and angiography-derived indices provide a comprehensive characterisation of CMD. The present narrative review aims to summarise current data relating to the diagnostic approach to CMD and provides details on the sequence that therapeutic management should follow.

Background Barth syndrome is a rare, life-threatening X-linked recessive mitochondrial disorder of lipid metabolism primarily affecting males. Previous research suggests that bezafibrate may ameliorate cellular lipid abnormalities and reduce cardiac dysfunction in an animal model. Objectives Estimate the effect of bezafibrate on clinical, biochemical, and quality-of-life outcomes. Investigate whether within-participant clinical changes parallel in vitro changes in cardiolipin ratio/profile and mitochondrial morphology when each participant’s cells are cultured with bezafibrate. Investigate as for objective 2, culturing each participant’s cells with resveratrol. Describe the most feasible methods and standardised outcome measures to optimise the conduct of future trials and evaluations in Barth syndrome. Describe features of the research infrastructure which optimised recruitment, retention and communication with families and people with Barth syndrome. Describe the perceptions of participants and their families about the research and any important potential barriers to participation. Design Randomised, placebo-controlled, crossover trial of bezafibrate versus placebo. Setting NHS hospital providing UK-wide Barth Syndrome Service. Participants Males aged ≥ 6 years with a confirmed diagnosis of Barth syndrome with stable cardiac status, able to swallow tablets of bezafibrate/placebo. Exclusions were: hypersensitivity or allergy to bezafibrate or any component of bezafibrate; hepatic, liver or renal dysfunction; gallbladder disease; or recent deterioration in general health. Interventions Fifteen weeks of bezafibrate in one period and placebo in a second period, or vice versa (randomly allocated), with at least a 1-month washout between periods. Main outcome measures The primary outcome was peak VO2; secondary outcomes were cardiac function rest and exercise echocardiography and magnetic resonance imaging, cardiolipin ratio, quality of life, dynamic skeletal muscle P-magnetic resonance spectroscopy, mitochondrial studies and neutrophil counts, and adverse events. Outcomes were measured at baseline and the end of each period. Results Eleven males were studied; all attended all three assessments. There was no difference in peak VO2 between periods (0.66 ml/kg/min lower with bezafibrate than placebo, 95% confidence interval 2.34 to 1.03; p = 0.43). There was a trend towards a higher left ventricular ejection fraction with bezafibrate when measured by echocardiography but not magnetic resonance imaging, and better echocardiography-derived rest longitudinal and circumferential strain with bezafibrate. There was no difference in quality of life or cardiolipin ratio between periods. Skeletal muscle 31P magnetic resonance spectroscopy was performed cross-sectionally and showed a trend to higher Tau and lower Qmax indices in the bazafibrate group. Two participants had serious, expected adverse reactions when taking bezafibrate; otherwise, bezafibrate was well tolerated. Limitations The sample size was very small; the bezafibrate dose may have been too low or 15 weeks too short to observe an effect; measurements of mitochondrial content and membrane potential were highly variable; P-magnetic resonance spectroscopy was available only at the final assessment. Conclusions This study did not show significant improvement in the primary and secondary outcomes with bezafibrate treatment. Future work Elamipretide, studied in a small crossover trial in the USA, is another potential intervention which may be worth evaluating in an international study. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information. Plain language summary Barth syndrome is a rare genetic syndrome with mutations in the tafazzin gene causing long-term effects in several organ systems, leading to significant lifelong comorbidities and a reduced quality of life. Barth syndrome shows an X-linked inheritance, hence it is almost exclusively present in males. Tafazzin gene mutations impair overall cell energy metabolism, and affected individuals show compromise of the immune system with a high risk for life-threatening infections, as well as cardiac dysfunction and cardiomyopathy, muscle and general fatigue, and generally reduced mobility also leading to psychological challenges and dysfunction. Currently, specific medical therapies are limited to symptomatic treatment, and drug therapies targeting the causative mitochondrial energy disturbance are urgently needed. This randomised controlled trial explored the use of oral bezafibrate, a licensed drug that can improve cell energy metabolism. Eleven male patients received either bezafibrate or a placebo for 4 months. Exercise capacity by cardiopulmonary exercise testing on a cycle ergometer, as the primary outcome measurement, as well as cardiac function by echocardiography and magnetic resonance imaging, and cellular anatomy and function by in vitro assays and microscopy, were measured before and after this 4-month period. Bezafibrate did not significantly improve exercise capacity, cardiac function or the cellular metabolism, although several cardiac function parameters showed slight improvements with bezafibrate treatment. No significant adverse effects were recorded. The limitations of the trial were its low participant number and the relatively short duration of the drug treatment phase. The trial did prove that complex randomised controlled drug trials are feasible in people with rare diseases. Adherence was good, with parents reporting few difficulties with pill swallowing. The qualitative interviews also found that the study was acceptable to participants and the burden of participating not too onerous. We hope the research can provide a template for future studies. Scientific summary Introduction Barth syndrome is a very rare, life-threatening, X-linked recessive genetic disease almost exclusively affecting young males, caused by abnormal lipids in mitochondria. The tafazzin gene (TAZ) encodes tafazzin, a phospholipid acyltransferase. Tafazzin transfers unsaturated fatty acids with acyl chains from phospholipids to monolysocardiolipin (MLCL) and regulates remodelling and maturation of cardiolipin, a phospholipid located exclusively in the inner mitochondrial membrane. Mature tetralinoleoyl-cardiolipin (L4-CL) is essential in the mitochondrial membrane for maintaining mitochondrial membrane potential, structural integrity of electron transport chain complexes and mitochondrial cristae architecture. Cardiolipin is a major constituent of inner mitochondrial membranes, and the major effects of the aberrant gene are on muscular tissues. Cardiac and skeletal manifestations of Barth syndrome are thought to result from impaired formation of respiratory chain super-complexes. TAZ mutations decrease L4-CL and increase intermediate species of MLCL, resulting in a marked increase in the MLCL : L4-CL ratio, which provides a highly sensitive and specific biochemical test for Barth syndrome. Barth syndrome is characterised by many gene mutations and profound phenotypic variability between affected patients within families and those in different families. The disease carries many risks and problems for its sufferers, as well as major healthcare costs. Almost one-third (30%) of living UK patients have undergone cardiac transplantation. Several patients who have died due to cardiac rejection or post-transplant lymphoproliferative disease had previously undergone cardiac transplantation. Other patients who have died deteriorated too fast to undergo transplantation or died of complications while awaiting transplantation. Neutropenia is another life-threatening issue. Two-thirds of UK patients are treated with granulocyte colony-stimulating factor by subcutaneous injection. Managing neutropenia in this disease is challenging, since patients have highly variable neutrophil counts, which prevents administration of a consistent daily dose and requires repeated blood counts and physician oversight. Exercise intolerance, lethargy and fatigue are universal, interfering with daily life, schoolwork and play and often necessitating use of a wheelchair. Patients cannot perform strenuous or demanding jobs. Many have major feeding problems from infancy through to adult life; for example, requiring feeding via gastrostomies. There can be rapid deterioration during periods of stable health despite expert medical care. Ventricular arrhythmia (tachycardia or fibrillation) affects 10% of adolescents and can cause sudden cardiac death at any time. There are no specific treatments for Barth syndrome. There is no evidence that standard medications for cardiomyopathy ameliorate long-term poor outcomes. Treatment is multidisciplinary and currently limited to treating intercurrent bacterial infections, bone marrow support, physiotherapy, nutritional support, management of heart failure and arrhythmia, and consideration for heart transplantation. Experiments using lymphoblasts from patients with Barth syndrome show that either bezafibrate or resveratrol can partially normalise the deranged cardiolipin ratio. This may be important, since some patients with Barth syndrome who lack neutropenia and tend to have good exercise tolerance have cardiolipin ratios intermediate between those of typical patients and normal individuals. Bezafibrate also improved left ventricular function and showed other benefits at supraphysiological doses in a TAZ knockdown mouse model. This trial was motivated by the need for disease-specific therapy to prevent morbidity, mortality, psychological distress, and disruption of quality of life (QoL) in affected patients and their families. An effective therapy also has the potential to generate savings for the NHS. Bezafibrate is a lipid-lowering drug used in adults and children, with a good safety record in long-term use. These characteristics made it a candidate for investigation. Bezafibrate has been reported to significantly ameliorate a mitochondrial myopathy in adults and shown promising results in several animal/human cellular models of mitochondrial disease. Several of the laboratory assays and clinical investigations proposed in this study were also considered potentially important beyond the scope of this specific study, to assess associations between genotype and phenotype and for future evaluations of therapies in Barth syndrome. Objectives Estimate the effect on clinical, biochemical and QoL outcome measures of bezafibrate compared to placebo. Investigate whether clinical improvements parallel in vitro changes in cardiolipin ratio and mitochondrial morphology in each participant’s cells when cultured with bezafibrate. Investigate whether clinical improvements and culture findings with bezafibrate parallel in vitro changes in each participant’s cells when exposed to resveratrol in laboratory culture. Describe the most feasible methods and standardised outcome measures for future trials. Describe features of the research infrastructure which optimised recruitment, retention and communication with participants and families. Describe participants’ and their families’ perceptions of research and important potential barriers to participation. Methods Study design and participants CARDIOlipin MANipulation trial (CARDIOMAN) was a double-blind, placebo-controlled crossover randomised trial. Treatment was given in two 15-week periods with a minimum of 1 month’s washout period between these when no treatment was given. Twenty-six males and one female with the disease were alive in the UK when the trial was designed. Males aged ≥ 6 years in the UK diagnosed with Barth syndrome were eligible. Exclusion criteria were: hypersensitivity to bezafibrate or component of the investigational medicinal product (IMP), photoallergic or phototoxic reaction to fibrate, unstable cardiac condition, cardiac chamber shortening fraction < 25% or significant decrease in shortening fraction in the preceding year, atrial or ventricular arrhythmia not stabilised by treatment, inability to swallow the IMP, hepatic dysfunction, renal impairment (creatinine clearance < 90 ml/min), gallbladder disease, recent unspecified significant deterioration in general health, prisoners and adults lacking capacity to provide informed consent. Randomisation and masking Participants were randomised to receive either bezafibrate then placebo, or the reverse order. Allocations were generated in advance by the Bristol Trials Centre and provided to the trial pharmacy which dispensed the IMP. All investigators, members of the research team (apart from pharmacy) and participants remained blind to treatment allocation. Intervention and procedures The intervention IMP was bezafibrate taken orally as 100-mg tablets. Children aged 6–9 years started on 100 mg once daily for the first 4 weeks and, if well tolerated, increased to 100 mg twice daily for the remaining 11 weeks. Children aged 10–17 years started on 200 mg once daily for the first 4 weeks and, if well tolerated, increased to 200 mg twice daily for the remaining 11 weeks. Adults (≥ 18 years) took 200 mg twice daily throughout. The comparator IMP was placebo taken orally as visually identical tablets and manufactured to be as similar as possible in taste and smell to the intervention. The IMP was prescribed at the start of the first period and again at the end of the first period for the second period. Outcomes All in vivo outcomes except magnetic resonance spectroscopy (MRS) were assessed three times: at baseline and in the final week of each treatment phase. The primary outcome measure was peak oxygen consumption on bicycle ergometry [peak volume of oxygen (VO2)]. Secondary outcomes were: MLCL/L4-CL ratio and cardiolipin profile in blood cells; phosphocreatine (PCr)/adenosine 5’ triphosphate (ATP) ratio in cardiac muscle on 31P MRS; skeletal muscle oxidative function/on 31P MRS; QoL [age-appropriate Pediatric Quality of Life Inventory (PedsQLTM) questionnaires]; absolute neutrophil count; amino acid expression (serum arginine and cysteine); cardiac function [left and right ventricular function: left ventricular ejection fraction (LVEF%), right ventricular ejection fraction (RVEF%); and 2-D longitudinal and circumferential strain at rest, peak exercise and after recovery]; mitochondrial size and number in lymphocytes; mitochondrial area in lymphocytes and as a proportion of cytoplasm area; mitochondrial function and cristae organisation in lymphocytes/neutrophils; arrhythmia profile from 12-lead electrocardiogram at rest and during exercise. Qualitative research methods explored participants’ and families’ experiences of the different interventions. Adverse events Serious adverse events (SAEs) and non-serious adverse events (AEs) were collected from participants from the time of consent until 1 month after the final period. Participants’ general practitioners were asked to inform the research team of suspected AEs. Participants were asked questions about SAEs/AEs at each research clinic visit and in monthly phone calls, including during the washout period. SAEs were reviewed by the Chief Investigator, who decided whether the SAE was related to bezafibrate. Statistical analysis A total of 20 males aged ≥ 6 years were potentially eligible. The sample size was dictated by the number of eligible boys willing to take part. The primary analysis estimated the difference in mean peak VO2 between placebo and bezafibrate periods (two-tailed 5% significance level). A sample size of 12 participants allowed the trial to detect a difference of 0.90 (within subject) standard deviations with 80% power. The statistical analysis plan (SAP) prespecified that all analyses should be conducted according to the intention-to-treat (ITT) principle. The ITT population comprised all participants and periods, according to the randomised allocations. The safety population comprised all randomised participants, according to the treatment received in each period, who received at least one dose of IMP. All statistical tests were two-sided and used a 5% significance level, except for interactions that used a 10% significance level. Treatment effects were estimated with 95% confidence intervals (CIs). No formal adjustment was made for multiple testing. The treatment effect for the primary outcome was analysed using mixed linear regression models, adjusting for period (fixed effect; exploring interactions where necessary) and participants (random effects). Model assumptions were tested using standard methods, and the carry-over effect was estimated by including treatment order. Treatment effects for continuously scaled secondary outcomes (prespecified in the SAP) were estimated and tested using the same methods. Results There was no statistically significant difference between bezafibrate and placebo in peak VO2, which was 0.66 ml/kg/min lower (95% CI −2.34 to 1.03; p = 0.43) with bezafibrate. There was a borderline statistically significant increase in LVEF% using echocardiography (3.72%, 95% CI −0.26% to 7.69%; p = 0.065) but no evidence of a difference when using magnetic resonance imaging (MRI) (0.15%, 95% CI −3.21% to 3.51%; p = 0.926). There was also no difference for RVEF% between bezafibrate and placebo (0.32, 95% CI −2.32 to 2.96; p = 0.801). Longitudinal and circumferential strain at rest were better (lower) with bezafibrate than with placebo; differences were –1.67 (95% CI −3.11 to −0.22; p = 0.026) and −2.72 (95% CI −5.03 to −0.40; p = 0.024) respectively. There was no difference in diastolic ratio at rest between bezafibrate and placebo, and no differences in strain or diastolic ratio at peak exercise or after 2 minutes’ recovery. All participants had sinus rhythm at rest and during exercise for all three time points. Magnetic resonance spectroscopy was only performed after the second period for 10 participants. PCr/ATP ratio in cardiac muscle was not collected. Cross-sectionally (five vs. five participants), MRS appeared to increase Tau and reduce Qmax parameters with bezafibrate compared to placebo. Monolysocardiolipin/L4-CL ratio did not differ between bezafibrate and placebo but deteriorated in the second period (20% higher, 95% CI 3% to 40%; p = 0.024). Neutrophil count also showed no difference between bezafibrate and placebo but increased in the second period (2.26, 95% CI 0.08 to 4.45; p = 0.043). Plasma cysteine increased with bezafibrate (32% higher, 95% CI 8% to 62%; p = 0.001) but plasma arginine did not (25% higher, 95% CI −10% to 72%; p = 0.180). Mitochondrial outcomes on blood samples did not show marked differences and were not formally compared. Quality-of-life scores were transformed to a 0–100 scale (higher being better). Bezafibrate had no effect on core (−3.41, 95% CI −8.67 to 1.86; p = 0.192) or fatigue (1.71, 95% CI −6.28 to 9.71; p = 0.659) QoL scores. Emerging themes identified in qualitative interviews were classified as overarching, related to lived experience with Barth syndrome, and trial participation and conduct. Participants and families were pleased to take part in the trial, viewing participation as ‘giving back’ to the medical community. No participant withdrew, and the trial was not perceived to be too onerous for families. Participating in the research gave both individuals and families a sense of responsibility for their condition, partly driven by appreciation for the Barth Syndrome Service and staff expertise. Monolysocardiolipin/L4-CL ratio in vitro was estimated from samples of cells incubated with control, bezafibrate or resveratrol. Each drug reduced the MLCL/L4-CL ratio, largely by increasing intermediate cardiolipin species, and more so with resveratrol than with bezafibrate. Ratios were nevertheless profoundly abnormal in comparison to patients with intermediate Barth phenotypes. Discussion Main findings: study results There was no clinically important or statistically significant improvement in peak VO2 with bezafibrate compared to placebo. There were inconsistent findings for LVEF% by method of measurement; echocardiography showed a borderline improvement that cardiac MRI did not demonstrate. Longitudinal and circumferential strain measurements were better at rest with bezafibrate, but not at peak exercise. There were no clinically important or statistically significant improvements in core or fatigue QoL domains. Plasma cysteine was significantly improved with bezafibrate treatment. Plasma arginine also increased but not significantly. Neutrophil count was unaffected and there was no significant change in cardiolipin ratio in participants’ blood with bezafibrate. There were no significant period effects except for MLCL/L4-CL ratio and neutrophil count, both increased in the second period. In vitro incubation of Epstein–Barr virus-transformed patient lymphoblasts with either bezafibrate or resveratrol resulted in improved MLCL/L4-CL ratios, an effect that was more profound with resveratrol. Treatment with this drug also resulted in a more obvious increase in intermediate MLCL species. Strengths and limitations Strengths of the trial are: randomisation and placebo blinding; crossover design; excellent retention; completeness of the data, good adherence and IMP tolerance. There were several limitations. The sample size (outside our control) was very small, and interpretation of effects for many secondary outcomes was challenging. Longer treatment duration or a higher bezafibrate dose might have produced better outcomes. Bezafibrate may have induced adverse reactions in some participants, inadvertently causing unblinding. The group of participants randomised to receive bezafibrate first was older than the group randomised to the opposite order, which may explain period effects. The electron microscopic and mitochondrial assessments proved problematic and were not completed in vitro. Measurements of mitochondrial content and membrane potential were highly variable. Amino acid levels were not assayed after fasting. Echocardiography images during exercise testing were often suboptimal. Lessons for the future Magnetic resonance spectroscopy in children is still exploratory, and protocols need to be better validated, but it is considered very promising as a potential objective functional outcome. Cardiolipin profile is not a good outcome for research, although it is appropriate for diagnosis because the Barth cardiolipin profile is so extremely different from a normal profile. Electron microscopy measurements of mitochondria should not be considered as outcomes in future trials. Peak VO2 should be the preferred current primary outcome because it is resistant to bias compared to other functional outcomes. Conclusion The trial did not show a significant treatment effect for the primary outcome, peak VO2. Some secondary outcomes such as systolic function measured by echocardiography and amino acid levels provided some evidence of benefit. The trial provided insights about trial methods and conduct in the context of a very rare paediatric disease that should inform future studies. Trial registration This trial is registered as ISRCTN58006579. Funding This award was funded by the National Institute for Health and Care Research (NIHR) Efficacy and Mechanism Evaluation (EME) programme (NIHR award ref: 12/205/56) and is published in full in Efficacy and Mechanism Evaluation; Vol. 11, No. 13. See the NIHR Funding and Awards website for further award information.

IntroductionIn systemic sclerosis (SSc), B-cells are activated and present in the skin and lung of patients where they can interact with fibroblasts. The precise impact and mechanisms of the interaction of B-cells and fibroblasts at the tissular level are poorly studied.ObjectiveWe investigated the impact and mechanisms of B-cell/fibroblast interactions in cocultures between B-cells from patients with SSc and 3-dimensional reconstituted healthy skin model including fibroblasts, keratinocytes and extracellular matrix.MethodsThe quantification and description of the B-cell infiltration in 3D cocultures were performed using cells imagery strategy and cytometry. The effect of coculture on the transcriptome of B-cells and fibroblasts was studied with bulk and single-cell RNA sequencing approaches. The mechanisms of this interaction were studied by blocking key cytokines like IL-6 and TNF.ResultsWe showed a significant infiltration of B-cells in the 3D healthy skin model. The amount but not the depth of infiltration was higher with B-cells from SSc patients and with activated B-cells. B-cell infiltrates were mainly composed of naïve and memory cells, whose frequencies differed depending on B-cells origin and activation state: infiltrated B-cells from patients with SSc showed an activated profile and an overexpression of immunoglobulin genes compared to circulating B-cells before infiltration. Our study has shown for the first time that activated B-cells modified the transcriptomic profile of both healthy and SSc fibroblasts, toward a pro-inflammatory (TNF and IL-17 signaling) and interferon profile, with a key role of the TNF pathway.ConclusionB-cells and 3D skin cocultures allowed the modelization of B-cells infiltration in tissues observed in SSc, uncovering an influence of the underlying disease and the activation state of B-cells. We showed a pro-inflammatory effect on skin fibroblasts and pro-activation effect on infiltrating B-cells during coculture. This reinforces the role of B-cells in SSc and provide potential targets for future therapeutic approach in this disease.

Summary: Human genetic studies of critical COVID-19 pneumonia have revealed the essential role of type I interferon-dependent innate immunity to SARS-CoV-2 infection. Conversely, an association between the HLA-B∗15:01 allele and asymptomatic SARS-CoV-2 infection in unvaccinated individuals was recently reported, suggesting a contribution of pre-existing T cell-dependent adaptive immunity. We report a lack of association of classical HLA alleles, including HLA-B∗15:01, with pre-omicron asymptomatic SARS-CoV-2 infection in unvaccinated participants in a prospective population-based study in the United States (191 asymptomatic vs. 945 symptomatic COVID-19 cases). Moreover, we found no such association in the international COVID Human Genetic Effort cohort (206 asymptomatic vs. 574 mild or moderate COVID-19 cases and 1,625 severe or critical COVID-19 cases). Finally, in the Human Challenge Characterisation study, the three HLA-B∗15:01 individuals infected with SARS-CoV-2 developed symptoms. As with other acute primary infections studied, no classical HLA alleles favoring an asymptomatic course of SARS-CoV-2 infection were identified.

There is growing evidence that in utero imbalance immune activity plays a role in the development of neurodevelopmental and psychiatric disorders in children. Mood dysregulation (MD) is a debilitating transnosographic syndrome whose underlying pathophysiological mechanisms could be revealed by studying its biomarkers using the Research Domain Criteria (RDoC) model. Our aim was to study the association between the network of cord serum cytokines, and mood dysregulation trajectories in offsprings between 3 and 8 years of age. We used the data of a study nested in the French birth cohort EDEN that took place from 2003 to 2014 and followed mother-child dyads from the second trimester of pregnancy until the children were 8 years of age. The 2002 mother-child dyads were recruited from the general population through their pregnancy follow-up in two French university hospitals. 871 of them were included in the nested cohort and cord serum cytokine levels were measured at birth. Children's mood dysregulation symptoms were assessed with the Strengths and Difficulties Questionnaire Dysregulation Profile at the ages 3, 5 and 8 years in order to model their mood dysregulation trajectories. Out of the 871 participating dyads, 53% of the children were male. 2.1% of the children presented a high mood dysregulation trajectory whereas the others were considered as physiological variations. We found a significant negative association between TNF-α cord serum levels and a high mood dysregulation trajectory when considering confounding factors such as maternal depression during pregnancy (adjusted Odds Ratio (aOR) = 0.35, 95% Confidence Interval (CI) [0.18–0.67]). Immune imbalance at birth could play a role in the onset of mood dysregulation symptoms. Our findings throw new light on putative immune mechanisms implicated in the development of mood dysregulation and should lead to future animal and epidemiological studies.

Abstract Background Diagnosis of children with type 1 diabetes (T1D) imposes an unprecedented burden on children and their caregivers. Objective To assess the burden of T1D on children and their informal caregivers, both after a recent diagnosis or after a longer duration of disease. Methods A series of systematic literature reviews were performed to explore the burden of T1D on children with the disease and their primary informal caregivers, based on the time of diagnosis. After the extraction of the qualitative and quantitative data from the included studies, two literature-based conceptual frameworks were developed: on the burden of pediatric T1D on children, and on informal caregivers. A third conceptual framework on the shared burden of pediatric T1D on both children and informal caregivers as part of the same family unit was also developed. Results The review of literature has identified a series of factors that affect the quality of life of children with T1D and their informal caregivers, with a direct impact on physical, emotional, and social outcomes. Generally, female patients and older adolescents experience more worry and stress that affects their quality of life. Other categories of factors affecting the child’s and caregiver’s burden include social, emotional, and physical factors, treatment-related and disease-related factors, as well as their coping abilities. Anxiety, depression, stress, and worry were commonly found among children and caregivers, starting with the diagnosis of T1D and continuing over time in relation to new challenges pertaining to aging or the disease duration. Conclusion T1D causes a significant burden to affected children and their caregivers, both independently and through transactional interaction within the family unit. Disease burden can be reduced by strengthening individuals for the benefit of the whole family.

Abstract Purpose Virtual reality (VR) is increasingly being used in health care. However, its use as part of therapy during prolonged inpatient treatments is less well established. This study assessed the experience of hemato-oncology inpatients, their caregivers or relatives and staff of a 20-min VR expedition to assess acceptability, safety, and opportunities to improve inpatient experience. Methods Through several familiarisation days, participants took part in a supervised 20-min trial of a 3-dimensional (3-D) VR escape using Google Wander™ delivered via an Oculus Quest 2 VR Headset™. Participants completed a validated survey of their VR experiences. Results Thirty-one patients, 10 staff members and 9 relatives or patient friends visited 55 unique countries, with 19 participants (38%) wishing to visit home, family, or friends. All participants enjoyed the experience, felt energised or had a sense of well-being following the immersion. One participant felt fatigued by the experience. No one found the experience disagreeable nor had difficulty in navigating within the device. No participant complained of nausea, with two patients experiencing dizziness and one developing a headache. Nine participants (18%) complained of eyestrain, while 12 participants (24%) complained of a sense of “head fullness”. None of the symptoms were perceived to need to shorten the immersion experience nor lasted beyond the immersion. Conclusion 3D-VR “holiday from hospital” can be used safely in acute inpatients with little supervised training. The broad acceptance of the technology, potentially providing a distraction from clinical care routines.

Abstract Ultrafast photoinduced phase transitions at room temperature, driven by a single laser shot and persisting long after stimuli, represent emerging routes for ultrafast control over materials’ properties. Time-resolved studies provide fundamental mechanistic insight into far-from-equilibrium electronic and structural dynamics. Here we study the photoinduced phase transformation of the Rb0.94Mn0.94Co0.06[Fe(CN)6]0.98 material, designed to exhibit a 75 K wide thermal hysteresis around room temperature between MnIIIFeII tetragonal and MnIIFeIII cubic phases. We developed a specific powder sample streaming technique to monitor by ultrafast X-ray diffraction the structural and symmetry changes. We show that the photoinduced polarons expand the lattice, while the tetragonal-to-cubic photoinduced phase transition occurs within 100 ps above threshold fluence. These results are rationalized within the framework of the Landau theory of phase transition as an elastically-driven and cooperative process. We foresee broad applications of the streaming powder technique to study non-reversible and ultrafast dynamics.

Over the last decade, distributed acoustic sensing (DAS) has received growing attention in the field of seismic acquisition and monitoring due to its potential high spatial sampling rate, low maintenance cost and high resistance to temperature and pressure. Despite its undeniable advantages, DAS faces some challenges, including a low signal-to-noise ratio, which partly results from the instrument-specific noise generated by DAS interrogators. We present a comparison between two deep learning approaches to address DAS hardware noise and enhance the quality of DAS data. These approaches have the advantage of including real instrumental noise in the neural network training dataset. For the supervised learning (SL) approach, real DAS instrumental noise measured on an acoustically isolated coil is added to synthetic data to generate training pairs of clean/noisy data. For the second method, the Noise2Noise (N2N) approach, the training is performed on noisy/noisy data pairs recorded simultaneously on the downgoing and upgoing parts of a downhole fiber-optic cable. Both approaches allow for the removal of unwanted noise that lies within the same frequency band of the useful signal, a result that cannot be achieved by conventional denoising techniques employing frequency filtering.

Exploring shallow mineral resources requires acquiring denser seismic data, for which Distributed Acoustic Sensing is an effective enabler and relevant to mining operations monitoring. Passive seismic can be of interest in characterizing the subsurface; however, dealing with large amounts of data pushes against the limits of existing computational systems and algorithms, especially for continuous monitoring. Hence, more than ever, novel data analysis methods are needed. In this article, we investigate using synthetic seismic data, paired with real noise recordings, as part of a supervised deep-learning neural network methodology to detect and locate induced seismic sources and explore their potential use to reconstruct subsurface properties. Challenges of this methodology were identified and addressed in the context of induced seismicity applications. Data acquisition and modelling were discussed, preparation workflows were implemented, and the method was demonstrated on synthetic data and tested on relevant seismic monitoring field dataset from the Otway CO2 injection site. Conducted tests confirmed the effects of time shifts, signal-to-noise ratios, and geometry mismatches on the performance of trained models. Those promising results showed the method’s applicability and paved the way for potential application to more field data, such as seismic while drilling.

ABSTRACT Objective: to interpret the meanings attributed to the health-related quality of life by caregivers of adolescents with type 1 diabetes mellitus. Methods: qualitative, descriptive-exploratory study of 14 caregivers of adolescents with diabetes developed at the reference outpatient clinic for endocrine diseases in a city in the state of Paraíba. Interviews were performed between May and September 2021. Inductive thematic analysis of the empirical material, and its interpretation in light of the concepts of health-related quality of life and family functioning were performed. Results: the meanings attributed by caregivers to the health-related quality of life of adolescents converged on the feeling of being healthy, healthy eating, satisfactory family income, family involvement in care and effective access to the care network. Final Considerations: knowledge of these meanings enables health professionals to develop strategies that meet the unique demands of caregivers experiencing this diagnosis.

BackgroundDengue is a major public health concern in Reunion Island, marked by recurrent epidemics, including successive outbreaks of dengue virus serotypes 1 and 2 (DENV1 and DENV2) with over 70,000 cases confirmed since 2017.Methodology/principal findingsIn this study, we used Oxford Nanopore NGS technology for sequencing virologically-confirmed samples and clinical isolates collected between 2012 and 2022 to investigate the molecular epidemiology and evolution of DENV in Reunion Island. Here, we generated and analyzed a total of 499 DENV1, 360 DENV2, and 18 DENV3 sequences. By phylogenetic analysis, we show that different genotypes and variants of DENV have circulated in the past decade that likely originated from Seychelles, Mayotte and Southeast Asia and highly affected areas in Asia and Africa.Conclusions/significanceDENV sequences from Reunion Island exhibit a high genetic diversity which suggests regular introductions of new viral lineages from various Indian Ocean islands. The insights from our phylogenetic analysis may inform local health authorities about the endemicity of DENV variants circulating in Reunion Island and may improve dengue management and surveillance. This work emphasizes the importance of strong local coordination and collaboration to inform public health stakeholders in Reunion Island, neighboring areas, and mainland France.

RESUMO O estudo identificou os contextos de aprendizagem profissional mais valorizados por 52 professores-treinadores de voleibol escolar. Para a coleta de dados foram utilizados um questionário sociodemográfico e a Escala de Contextos de Aprendizagem de Treinadores. Os dados foram analisados no software SPSS, versão 20.0, adotando o nível de significância de 95% (p

Abstract Introduction The transition from hospital to home is often suboptimal, resulting in patients not receiving the necessary allied healthcare after discharge. This may, in turn, lead to delayed recovery, a higher number of readmissions, more emergency department visits and an increase in mortality and healthcare costs. This study aimed to gain insight into patients' experiences, perceptions, and needs regarding hospital‐to‐home transition, focusing on allied healthcare as a first step towards the development of a transitional integrated allied healthcare pathway for patients with complex care needs after hospital discharge. Methods We conducted semistructured interviews with patients. Participants were recruited from universities and general hospitals in the Amsterdam region between May and July 2023. They were eligible if they (1) were discharged from the hospital minimally 3 and maximally 12 months after admission to an oncologic surgery department, internal medicine department, intensive care unit, or trauma centre, (2) received hospital‐based care from at least one allied healthcare provider, who visited the patient at least twice during hospital admission, (3) spoke Dutch or English and (4) were 18 years or older. Interviews were audio‐recorded and transcribed verbatim. We performed a thematic analysis of the interview data. Results Nineteen patients were interviewed. Three themes emerged from the analysis. ‘Allied healthcare support during transition’ depicts patients' positive experiences when they felt supported by allied health professionals during the hospital‐to‐home transition. ‘Patient and family involvement’ illustrates how much patients value the involvement of their family members during discharge planning. ‘Information recall and processing’ portrays the challenges of understanding and remembering overwhelming amounts of information, sometimes unclear and provided at the wrong moment. Overall, patients' experiences of transitional care were positive when they were involved in the discharge process. Negative experiences occurred when their preferences for postdischarge communication were ignored. Conclusions This study suggests that allied health professionals need to continuously collaborate and communicate with each other to provide patients and their families with the personalized support they need. To provide high‐quality and person‐centred care, it is essential to consider how, when, and what information to provide to patients and their families to allow them to contribute to their recovery actively. Patient or Public Contribution The interview guide for this manuscript was developed with the assistance of patients, who reviewed it and provided us with feedback. Furthermore, patients provided us with their valuable lived experiences by participating in the interviews conducted for this study.

This paper contributes to the understanding of market categorisation processes. More specifically, it analyses the evolution of the independent music category, characterised as a fuzzy category by its instability and as an alternative category by its power relations with the dominant mainstream music category. Based on a sociohistorical approach, we show how external forces such as boundary reconfigurations on the one hand and internal forces such as tension around category representations on the other shape the definition and evolution of the independent music market category. Our findings show the joint action of these dynamics in the emergence and evolution of alternative categories. They highlight the interest of simultaneously examining these multiple dynamics and their relationships in the study of market categories. Our paper also reveals the strategic and ideological issues associated with the alternative – mainstream dialectic, which constitutes a key factor in the structuring and evolution of many other industries.

Abstract Objectives Determine factors associated with delayed endoscopic sinus surgery (ESS) in patients with chronic rhinosinusitis (CRS). Methods This is a retrospective cohort study conducted at a tertiary care academic center. Patients were included in the study if they were at least 18 years old and underwent surgery for CRS. Electronic medical records were retrospectively reviewed to collect demographic and clinical data. Patients with CRS secondary to another pathology such as malignancy were excluded. Multiple linear regression was performed to determine factors associated with the number of days between a patient's preoperative consultation and the date of surgery. Results A total of 103 patients with a mean age of 46.6 ± 16.8 years were included in the analysis; 51.5% of patients were females, 46.6% identified as White, and 29.1% identified as Hispanic. The majority of patients (67.0%) had preferred provider organization health insurance; 43.7% of patients had nasal polyps, 70.9% had a deviated nasal septum, and the mean preoperative Sinonasal Outcomes Test‐22 (SNOT‐22) score was 41.0 ± 23.8. The mean time to surgery after the final preoperative visit was 71.7 days ± 65.6 days. Hispanic ethnicity was associated with increased time to surgery (p

Abstract Background The demand for 68Ga-labeled radiotracers has significantly increased in the past decade, driven by the development of diversified imaging tracers, such as FAPI derivatives, PSMA-11, DOTA-TOC, and DOTA-TATE. These tracers have exhibited promising results in theranostic applications, fueling interest in exploring them for clinical use. Among these probes, 68Ga-labeled FAPI-46 and DOTA-TOC have emerged as key players due to their ability to diagnose a broad spectrum of cancers ([68Ga]Ga-FAPI-46) in late-phase studies, whereas [68Ga]Ga-DOTA-TOC is clinically approved for neuroendocrine tumors. To facilitate their production, we leveraged a microfluidic cassette-based iMiDEV radiosynthesizer, enabling the synthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC based on a dose-on-demand (DOD) approach. Results Different mixing techniques were explored to influence radiochemical yield. We achieved decay-corrected yield of 44 ± 5% for [68Ga]Ga-FAPI-46 and 46 ± 7% for [68Ga]Ga-DOTA-TOC in approximately 30 min. The radiochemical purities (HPLC) of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC were 98.2 ± 0.2% and 98.4 ± 0.9%, respectively. All the quality control results complied with European Pharmacopoeia quality standards. We optimized various parameters, including 68Ga trapping and elution, cassette batches, passive mixing in the reactor, and solid-phase extraction (SPE) purification and formulation. The developed synthesis method reduced the amount of precursor and other chemicals required for synthesis compared to conventional radiosynthesizers. Conclusions The microfluidic-based approach enabled the implementation of radiosynthesis of [68Ga]Ga-FAPI-46 and [68Ga]Ga-DOTA-TOC on the iMiDEV™ microfluidic module, paving the way for their use in preclinical and clinical applications. The microfluidic synthesis approach utilized 2–3 times less precursor than cassette-based conventional synthesis. The synthesis method was also successfully validated in a similar microfluidic iMiDEV module at a different research center for the synthesis of [68Ga]Ga-FAPI-46 with limited runs. Our study demonstrated the potential of microfluidic methods for efficient and reliable radiometal-based radiopharmaceutical synthesis, contributing valuable insights for future advancements in this field and paving the way for routine clinical applications in the near future.

Abstract Gender identity refers to the consciousness of being a man, a woman or other condition. Although it is generally congruent with the sex assigned at birth, for some people it is not. If the incongruity is distressing, it is defined as gender dysphoria (GD). Here, we measured whole-genome DNA methylation by the Illumina © Infinium Human Methylation 850k array and reported its correlation with cortical thickness (CTh) in 22 transgender men (TM) experiencing GD versus 25 cisgender men (CM) and 28 cisgender women (CW). With respect to the methylation analysis, TM vs. CW showed significant differences in 35 CpGs, while 2155 CpGs were found when TM vs. CM were compared. With respect to correlation analysis, TM showed differences in methylation of CBLL1 and DLG1 genes that correlated with global and left hemisphere CTh. Both genes were hypomethylated in TM compared to the cisgender groups. Early onset TM showed a positive correlation between CBLL1 and several cortical regions in the frontal (left caudal middle frontal), temporal (right inferior temporal, left fusiform) and parietal cortices (left supramarginal and right paracentral). This is the first study relating CBLL1 methylation with CTh in transgender persons and supports a neurodevelopmental hypothesis of gender identity.

PolandâLithuania served as Europeâs grain basket for centuries, playing a vital role in feeding its neighbours during times of climatic adversity. However, its ecological abundance also attracted hostile intentions. In the early 1770s, the territory experienced a twin catastrophe: a deep political crisis coinciding with a severe climate anomaly. This paper examines the interaction between climate and conflict during a period typically analysed only from the perspective of political history. It aims to reconnect significant state events, such as civil war, occupation, and partition, with their socio-ecological context, including harvest failures, famine, and epidemics. This approach challenges deterministic simplifications of climateâconflict relations and emphasises the diverse range of human responses to climatic impacts, ranging from desperation to appropriation.

Abstract Prediction of spontaneous preterm birth in asymptomatic women remains a great challenge for the public health system. The aim of the study was to determine the informational value of EG-VEGF circulating levels for prediction of spontaneous preterm birth in the second and third trimesters in pregnant women at high risk for placenta-mediated complications. A prospective multicenter cohort study including 200 pregnant patients with five-serum sampling per patient. Women with spontaneous preterm birth have higher concentrations of serum EG-VEGF than uncomplicated patients at 24 weeks, 28 weeks and 32 weeks (p = 0.03, 0.02 and

The BK polyomavirus (BKPyV) is a small DNA non-enveloped virus whose infection is asymptomatic in most of the world’s adult population. However, in cases of immunosuppression, the reactivation of the virus can cause various complications, and in particular, nephropathies in kidney transplant recipients or hemorrhagic cystitis in bone marrow transplant recipients. Recently, it was demonstrated that BKPyV virions can use extracellular vesicles to collectively traffic in and out of cells, thus exiting producing cells without cell lysis and entering target cells by diversified entry routes. By a comparison to other naked viruses, we investigated the possibility that BKPyV virions recruit the Endosomal-Sorting Complexes Required for Transport (ESCRT) machinery through late domains in order to hijack extracellular vesicles. We identified a single potential late domain in the BKPyV structural proteins, a YPX3L motif in the VP1 protein, and used pseudovirions to study the effect of point mutations found in a BKPyV clinical isolate or known to ablate the interaction of such a domain with the ESCRT machinery. Our results suggest that this domain is not involved in BKPyV association with extracellular vesicles but is crucial for capsomere interaction and thus viral particle assembly.

This study first presents the development and the experimental validation of a numerical model of a semi-closed greenhouse using a dynamic thermal simulation. The second objective was to identify the influential parameters on the indoor climate and to calculate the heating demand of the greenhouse. The model reproduced the behavior of a full-scale experimental greenhouse in Carquefou (France). The comparison with experimental measurements recorded over an entire season of tomato cultivation validated the numerical model. The result of the simulated energy consumption was 310 kWh/m2/year with a relative error of 3.5%. The parametric study identified that the evapotranspiration power and ventilation rate were the most influential input variables, accounting for 50% and 32%, respectively, of the heating demand. The most sensitive output variable was indoor humidity. The presence of a thermal buffer zone all around the greenhouse reduced the energy consumption by 48%, and thermal/shading screens reduced it by 30%. The final objective was to assess the amount of heat recovery potential over the year and each week, depending on the energy storage strategy. Around 43 kWh/m2/year can be recovered over the year, leading to a potential energy savings of 24%.

Abstract Systemic sclerosis (SSc) is the most severe systemic autoimmune disease with currently no cure. Intravenous immunoglobulins (IVIg) are an attractive candidate in this disease to counteract inflammation and fibrosis but data are scarce and conflicting. This study, assessed the effects of IVIg in a murine HOCl-induced model of SSc. We showed that IVIg prevented skin inflammation and fibrosis, by mitigating the immune cell infiltration (p = 0.04), proinflammatory cytokines gene overexpression (IL1β, p = 0.04; TNFα, p = 0.04; IL6, p = 0.05), skin and dermal thickening (p = 0.003 at d21 and p = 0.0003 at d42), the expression markers of fibrosis, such as αSMA (p = 0.031 for mRNA and p = 0.05 for protein), collagen (p = 0.05 for mRNA and p = 0.04 for protein, p = 0.05 for the hydroxyproline content) and fibronectin (p = 0.033 for mRNA). Moreover, IVIg prevented HOCl-induced alterations in splenic cell homeostasis. When administered in curative mode, despite their ability to reduce skin and dermal thickness (p

Abstract Background Cardiac surgery-associated acute kidney injury (CSA-AKI) is frequent. While two network meta-analyses assessed the impact of pharmacological interventions to prevent CSA-AKI, none focused on non-pharmacological interventions. We aim to assess the effectiveness of non-pharmacological interventions to reduce the incidence of CSA-AKI. Methods We searched PubMed, Embase, Central and clinical trial registries from January 1, 2004 (first consensus definition of AKI) to July 1, 2023. Additionally, we conducted manual screening of abstracts of major anesthesia and intensive care conferences over the last 5 years and reference lists of relevant studies. We selected all randomized controlled trials (RCTs) assessing a non-pharmacological intervention to reduce the incidence of CSA-AKI, without language restriction. We excluded RCTs of heart transplantation or involving a pediatric population. The primary outcome variable was CSA-AKI. Two reviewers independently identified trials, extracted data and assessed risk of bias. Random-effects meta-analyses were conducted to calculate risk ratios (RRs) with 95% confidence intervals (CIs). We used the Grading of Recommendations Assessment, Development, and Evaluation to assess the quality of evidence. Results We included 86 trials (25,855 patients) evaluating 10 non-pharmacological interventions to reduce the incidence of CSA-AKI. No intervention had high-quality evidence to reduce CSA-AKI. Two interventions were associated with a significant reduction in CSA-AKI incidence, with moderate quality of evidence: goal-directed perfusion (RR, 0.55 [95% CI 0.40–0.76], I 2 = 0%; P het = 0.44) and remote ischemic preconditioning (RR, 0.86 [0.78–0.95]; I 2 = 23%; P het = 0.07). Pulsatile flow during cardiopulmonary bypass was associated with a significant reduction in CSA-AKI incidence but with very low quality of evidence (RR = 0.69 [0.48; 0.99]; I 2 = 53%; P het

Abstract Background The COVID-19 pandemic disproportionately impacted long-term care and assisted living (LTC/AL) facilities in Canada, where infection prevention and control (IPAC) programs had been suboptimal. We aimed to identify barriers affecting healthcare workers’ (HCW) adherence to IPAC practices during the pandemic in British Columbia in LTC/AL compared to acute care settings. Methods We conducted a web-based survey of direct care providers and IPAC professionals across BC from August to September 2021, focused on knowledge and attitudes toward IPAC within the context of the COVID-19 pandemic, and barriers that affected respondents’ abilities to follow IPAC practices throughout the pandemic. Results The final analysis included 896 acute care respondents and 441 from LTC/AL. More LTC/AL respondents reported experiencing the following barriers: following IPAC guidance was of lower priority compared to other tasks (29.1% vs. 14.7%, FDR = 0.001) and not their responsibility (28.0% vs. 11.2%, FDR = 0.001); limited supplies for personal protective equipment (PPE) (49.0% vs. 33.6%, FDR = 0.001), hand hygiene products (42.2% vs. 28.8%, FDR = 0.001), and cleaning/disinfection products (44.1% vs. 30.3%, FDR = 0.001); deficits in IPAC leadership support (46.2% vs. 38.9%, FDR = 0.012), IPAC education and training (46.9% vs. 32.0%, FDR = 0.001), and patient care knowledge for managing COVID-19 infections (46.6% vs. 36.0%, FDR = 0.001). Conclusions This survey found that barriers to HCWs’ adherence to IPAC practices during the COVID-19 pandemic were different in LTC/AL settings compared to acute care. Improvement efforts should focus on strengthening IPAC programs in LTC/AL, particularly enhanced IPAC staffing/leadership, increased training and education, and improving access to PPE, hand hygiene, and cleaning products.

Abstract Background Over the past decades, there has been a growing international interest in user involvement in healthcare research. However, evidence on the management and impact of patient and public involvement in Nordic healthcare research remains limited. Objective The aim was to explore and delineate the current state, practice, and impact of patient and public involvement in healthcare research across different areas of healthcare and patient populations in the Nordic countries. Methods We conducted a scoping review using nine scientific databases and gray literature from 1992–2023. Sources were categorized as empirical or non-empirical. We used the Guidance for Reporting Involvement of Patients and the Public Short Form 2 checklist for reporting of patient and public involvement in healthcare research and the Preferred Reporting Items for Systematic reviews and Meta-Analyses extension for Scoping Reviews. Results A total of 56 publications were included, consisting of 39 empirical and 17 non-empirical sources. Gray literature varied among countries and institutions encompassing different types of documents. We found an increase in the number of publications on patient and public involvement in Nordic healthcare research. This was evidenced by the growing number of references and institutional initiatives intended at involving the public, indicating the increasing emphasis on patient and public involvement in Nordic healthcare research. The terminology used to describe patient and public involvement varied over time. However, there has been a gradual narrowing down of terms as the concept of PPI has become more integrated into research practices, particularly with the involvement of funding agencies. Conclusion The utilization of patient and public involvement in Nordic healthcare research has substantially increased, proliferated, and gained widespread acceptance across diverse healthcare domains. The variety of approaches challenged our scoping review in terms of systematic description and impact. Patient and public involvement was applied in one or more research stages using different methodologies and terms. International agreement on terms and definitions is needed for reliable interpretation of the use of patient and public involvement in Nordic healthcare research.

Abstract Background Haloperidol is frequently used in critically ill patients with delirium, but evidence for its effects has been sparse and inconclusive. By including recent trials, we updated a systematic review assessing effects of haloperidol on mortality and serious adverse events in critically ill patients with delirium. Methods This is an updated systematic review with meta-analysis and trial sequential analysis of randomised clinical trials investigating haloperidol versus placebo or any comparator in critically ill patients with delirium. We adhered to the Cochrane handbook, the PRISMA guidelines and the grading of recommendations assessment, development and evaluation statements. The primary outcomes were all-cause mortality and proportion of patients with one or more serious adverse events or reactions (SAEs/SARs). Secondary outcomes were days alive without delirium or coma, delirium severity, cognitive function and health-related quality of life. Results We included 11 RCTs with 15 comparisons (n = 2200); five were placebo-controlled. The relative risk for mortality with haloperidol versus placebo was 0.89; 96.7% CI 0.77 to 1.03; I 2 = 0% (moderate-certainty evidence) and for proportion of patients experiencing SAEs/SARs 0.94; 96.7% CI 0.81 to 1.10; I 2 = 18% (low-certainty evidence). We found no difference in days alive without delirium or coma (moderate-certainty evidence). We found sparse data for other secondary outcomes and other comparators than placebo. Conclusions Haloperidol may reduce mortality and likely result in little to no change in the occurrence of SAEs/SARs compared with placebo in critically ill patients with delirium. However, the results were not statistically significant and more trial data are needed to provide higher certainty for the effects of haloperidol in these patients. Trial registration: CRD42017081133, date of registration 28 November 2017.

Abstract Background Patients with recurrent or metastatic head and neck squamous cell carcinoma (R/M-HNSCC) have a poor prognosis and limited therapeutic options. Immune checkpoint inhibitors (ICIs) are effective in patients with tumor progression

Abstract Tamoxifen, a selective estrogen receptor modulator, is used to treat hormone receptor‐positive breast cancer. Tamoxifen acts as a prodrug, with its primary therapeutic effect mediated by its principal metabolite, endoxifen. However, tamoxifen has complex pharmacokinetics involving several drug‐metabolizing enzymes and transporters influencing its disposition. Genes encoding enzymes involved in tamoxifen disposition exhibit genetic polymorphisms which vary widely across world populations. This review highlights the lack of data on tamoxifen pharmacogenetics among African populations. Gaps in data are described in this study with the purpose that future research can address this dearth of research on the pharmacogenetics of tamoxifen among African breast cancer patients. Initiatives such as the African Pharmacogenomics Network (APN) are crucial in promoting comprehensive pharmacogenetics studies to pinpoint important variants in pharmacogenes that could be used to reduce toxicity and improve efficacy.

A key characteristic of free-range chicken farming is to enable chickens to spend time outdoors. However, each chicken may use the available areas for roaming in variable ways. To check if, and how, broilers use their outdoor range at an individual level, we need to reliably characterise range use behaviour. Traditional methods relying on visual scans require significant time investment and only provide discontinuous information. Passive RFID (Radio Frequency Identification) systems enable tracking individually tagged chickens’ when they go through pop-holes; hence, they only provide partial information on the movements of individual chickens. Here, we describe a new method to measure chickens’ range use and test its reliability on three ranges each containing a different breed. We used an active RFID system to localise chickens in their barn, or in one of nine zones of their range, every 30 seconds and assessed range-use behaviour in 600 chickens belonging to three breeds of slow- or medium-growing broilers used for outdoor production (all

BRCA1/2 genes are part of homologous recombination (HR) DNA repair pathways in charge of error-free double-strand break (DSB) repair. Loss-of-function mutations of BRCA1/2 genes have been associated for a long time with breast and ovarian cancer hereditary syndrome. Recently, polyadenosine diphosphate–ribose polymerase inhibitors (PARPi) have revolutionized the therapeutic landscape of BRCA1/2-mutated tumors, especially of BRCA1/2 high-grade serous ovarian cancer (HGSC), taking advantage of HR deficiency through the synthetic lethality concept. However, PARPi efficiency differs among patients, and most of them will develop resistance, particularly in the relapse setting. In the current proposal, we aim to review primary and secondary resistance to PARPi in HGSC owing to BRCA1/2 alterations. Of note, as several mechanisms of primary or secondary resistance to PARPi have been described, BRCA1/2 reversion mutations that restore HR pathways are by far the most reported. First, the type and location of the BRCA1/2 primary mutation have been associated with PARPi and platinum-salt sensitivity and impact the probability of the occurrence and the type of secondary reversion mutation. Furthermore, the presence of multiple reversion mutations and the variation of allelic frequency under treatment underline the role of intratumor heterogeneity (ITH) in treatment resistance. Of note, circulating tumor DNA might help us to detect and characterize reversion mutations and ITH to finally refine the treatment strategy. Importantly, forthcoming therapeutic strategies, including combination with antiangiogenics or with targeted therapies, may help us delay and overcome PARPi resistance secondary to BRCA1/2 reversion mutations. Also, progression despite PARPi therapy does not preclude PARPi rechallenge in selected patients.