Reassessing the chronic lymphocytic leukemia International Prognostic Index in the era of targeted therapies.

ABSTRACT: We evaluated the chronic lymphocytic leukemia International Prognostic Index (CLL-IPI) in patients with CLL treated first line with targeted drugs (n = 991) or chemoimmunotherapy (n = 1256). With a median observation time of 40.5 months, the 3-year progression-free survival (PFS) rates for targeted drug-treated patients varied by CLL-IPI risk group: 96.5% (low), 87.6% (intermediate), 82.4% (high), and 78.7% (very high). Differences between consecutive CLL-IPI risk groups were observed for intermediate vs low and high vs intermediate, but not very high vs high. CLL-IPI factors ß2-microglobulin, immunoglobulin heavy variable (IGHV) status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS) rates by CLL-IPI risk groups were 100%, 96%, 93.9%, and 89.4%, respectively, with no differences between consecutive risk groups. Age, Binet stage, ß2-microglobulin, and TP53 status each retained prognostic value for OS. In chemoimmunotherapy patients (median observation time, 66.9 months), 3-year PFS rates for CLL-IPI risk groups were 78.1%, 51.4%, 40.1%, and 16.5%, respectively; corresponding 3-year OS rates were 97.4%, 93.1%, 81.8%, and 57.3%. In a matched-pair analysis, PFS differences in targeted therapies (n = 812) vs chemoimmunotherapy (n = 812) across all risk groups and OS differences in all but patients at low risk were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs, but its impact in predicting survival appears diminished. Targeted therapies showed enhanced outcomes over chemoimmunotherapy, highlighting their effectiveness across various risk groups. Our findings support ongoing assessment of prognostic tools in CLL treatment evolution. These trials were registered at www.ClinicalTrials.gov as #NCT02345863, #NCT02401503, #NCT02689141, #NCT02445131, #NCT02758665, #NCT02950051, #NCT02242942, #NCT00262782, #NCT00281918, and #NCT01010061.

High karyotypic complexity is an independent prognostic factor in patients with CLL treated with venetoclax combinations.

Complex karyotypes have been associated with inferior outcomes in chronic lymphocytic leukemia (CLL) treated with chemoimmunotherapy (CIT), whereas their prognostic impact in the context of venetoclax-based treatments is still debated. In this prospective analysis on karyotype complexity in CLL, we evaluated the impact of complex (≥3 chromosomal aberrations [CAs], CKTs) and highly complex karyotypes (≥5 CAs; hCKTs) as well as specific aberrations in previously untreated patients without TP53 aberrations undergoing either CIT or time-limited venetoclax-based therapies in the phase 3 GAIA/CLL13 trial. Karyotype analyses were available for 895 of 926 patients (96.7%), of whom 153 (17%) had a CKT and 43 (5%) hCKT. In the CIT arm, CKT was associated with shorter progression-free survival (PFS) (hazard ratio [HR] 2.58; 95% confidence interval [95% CI], 1.54-4.32; P < .001) and overall survival (HR, 3.25; 95% CI, 1.03-10.26; P = .044). In the pooled venetoclax arms, a multivariable analysis identified hCKTs (HR, 1.96; 95% CI, 1.03-3.72; P = .041), but not CKTs, as independent adverse prognosticators for PFS. The presence of translocations (unbalanced and/or balanced) was also independently associated with shorter PFSs in the venetoclax arms. CIT led to the acquisition of additional CAs (mean CAs, 2.0-3.4; from baseline to CLL progression), whereas karyotype complexity remained stable after venetoclax-based treatments (2.0, both time points). This analysis establishes highly complex karyotypes and translocations as adverse prognostic factors in the context of venetoclax-based combination treatments. The findings of this study support the incorporation of karyotyping into the standard diagnostic workup of CLL, because it identifies patients at high risk of poor treatment outcomes and thereby improves prognostication. This trial was registered at www.clinicaltrials.gov as #NCT02950051.

Fixed-duration venetoclax plus obinutuzumab improves quality of life and geriatric impairments in FCR-unfit patients with CLL.

Chronic lymphocytic leukemia (CLL)-related symptoms and morbidity related to the advanced age at diagnosis impairs the well-being of older adult patients. Therefore, it is essential to tailor treatment according to geriatric characteristics and aim for an improvement in health-related quality of life (HRQoL) as a primary treatment goal. In the HOVON139/GiVe trial, 12 cycles of fixed-duration venetoclax plus obinutuzumab (Ven-O) were shown to be effective and tolerable in FCR (fludarabine, cyclophosphamide, rituximab)-unfit patients with CLL (n = 67). However, prolonged venetoclax exposure as consolidation treatment led to increased toxicity with limited effect on minimal residual disease. To assess the impact of geriatric assessment on treatment outcomes and the patients' HRQoL, patient-reported outcomes (PROs), including function, depression, cognition, nutrition, physical performance, muscle parameters, comorbidities, and the European Organization for Research and Treatment of Cancer C30 and CLL17 questionnaires were assessed. At baseline, geriatric impairments were present in >90% of patients and ≥2 impairments present in 60% of patients predicted grade ≥3 nonhematological toxicity. During treatment, the number of geriatric impairments diminished significantly and clinically relevant improvements in HRQoL subscales were reached for global health status, physical functioning, role functioning, emotional functioning, fatigue, dyspnea, physical condition or fatigue, and worries or fears related to health and functioning. These improvements were comparable for patients receiving venetoclax consolidation and patients in whom treatment could mostly be discontinued. Collectively, frontline fixed-duration Ven-O improves overall PROs in older, unfit patients with CLL with and without geriatric impairments. This study was registered at EudraCT as 2015-004985-27 and the Netherlands Trial Register as NTR6043.

Influence of a sexism and sexual harassment prevention course on medical students' perceptions of and responses to problematic situations.

BACKGROUND: Issues of sexism and sexual harassment within the medical field are widespread. The aim of his study was to describe the influence of a training course on the prevention of sexism and sexual harassment on medical students' perceptions and responses to problematic situations in the workplace. METHODS: We performed a secondary analysis of the transcripts of 16 medical students' interviews. The data were initially gathered as part of an external evaluation of the course. We decided to further explore these with a focus on potential changes about sexism and sexual harassment awareness induced by the course. Data were analyzed using qualitative thematic analysis. RESULTS: Most medical students were aware of the existence of sexism and sexual harassment in the medical environment before the course but were not always able to delineate what could be considered as such or not. The course allowed them to broaden their ability to identify problematic situations, that were somewhat "trivialized" before, and to set a lower cut-off when judging what constitutes sexism or sexual harassment. It also provided them with tools on how to react when confronted to these situations, as well as resources to seek help. However, students stressed the importance of such courses also being offered to medical staff higher up in the hierarchy, as they are the ones in a position of power. CONCLUSIONS: The course helped students to better identify and react to sexism and sexual harassment. However, given students' lack of power within the hierarchy, efforts to prevent sexism and sexual harassment must be undertaken at an institutional level to allow for change in the system as a whole.

Broken bones and apple brandy: resilience and sensemaking of general practitioners and their at-risk patients during the COVID-19 pandemic in Switzerland.

In early 2020, when the first COVID-19 cases were confirmed in Switzerland, the federal government started implementing measures such as national stay-at-home recommendations and a strict limitation of health care services use. General practitioners (GPs) and their at-risk patients faced similar uncertainties and grappled with subsequent sensemaking of the unprecedented situation. Qualitative interviews with 24 GPs and 37 at-risk patients were conducted which were analyzed using thematic analysis. Weick's (1993) four sources of -resilience - improvisation, virtual role systems, attitudes of wisdom and respectful interaction - heuristically guide the exploration of on-the-ground experiences and informal ways GPs and their at-risk patients sought to ensure continuity of primary care. GPs used their metaphorical Swiss army knives of learned tools as well as existing knowledge and relationships to adapt to the extenuating circumstances. Through improvisation, GPs and patients found pragmatic solutions, such as using local farmer apple brandy as disinfectant or at-home treatments of clavicle fractures. Through virtual role systems, GPs and patients came to terms with new and shifting roles, such as "good soldier" and "at-risk patient" categorizations. Both parties adopted attitudes of wisdom by accepting that they could not know everything. They also diversified their sources of information through personal relationships, formal networks, and the internet. The GP-patient relationship grew in importance through respectful interaction, and intersubjective reflection helped make sense of shifting roles and ambiguous guidelines. The empirical analysis of this paper contributes to theoretical considerations of sensemaking, resilience, crisis settings and health systems.

Minimal residual disease-guided stop and start of venetoclax plus ibrutinib for patients with relapsed or refractory chronic lymphocytic leukaemia (HOVON141/VISION): primary analysis of an open-label, randomised, phase 2 trial.

BACKGROUND: Targeted time-limited treatment options are needed for patients with relapsed or refractory chronic lymphocytic leukaemia. The aim of this study was to investigate the efficacy of minimal residual disease (MRD)-guided, time-limited ibrutinib plus venetoclax treatment in this patient group. METHODS: HOVON141/VISION was an open-label, randomised, phase 2 trial conducted in 47 hospitals in Belgium, Denmark, Finland, the Netherlands, Norway, and Sweden. Eligible participants were aged 18 years or older with previously treated chronic lymphocytic leukaemia with or without TP53 aberrations; had not been exposed to Bruton tyrosine-kinase inhibitors or BCL2 inhibitors; had a creatinine clearance rate of 30 mL/min or more; and required treatment according to International Workshop on Chronic Lymphocytic Leukemia 2018 criteria. Participants with undetectable MRD (<10-4; less than one chronic lymphocytic leukaemia cell per 10 000 leukocytes) in peripheral blood and bone marrow after 15 28-day cycles of oral ibrutinib (420 mg once daily) plus oral venetoclax (weekly ramp-up 20 mg, 50 mg, 100 mg, 200 mg, up to 400 mg once daily) were randomly assigned (1:2) to ibrutinib maintenance or treatment cessation. Patients who were MRD positive continued to receive ibrutinib monotherapy. Patients who became MRD (>10-2) during observation reinitiated treatment with ibrutinib plus venetoclax. The primary endpoint was progression-free survival at 12 months after random assignment in the treatment cessation group. Progression-free survival was analysed in the intention-to-treat population. All patients who received at least one dose of study drug were included in the safety assessment. The study is registered at ClinicalTrials.gov, NCT03226301, and is active but not recruiting. FINDINGS: Between July 12, 2017, and Jan 21, 2019, 230 patients were enrolled, 225 of whom were eligible. 188 (84%) of 225 completed treatment with ibrutinib plus venetoclax and were tested for MRD at cycle 15. After cycle 15, 78 (35%) patients had undetectable MRD and 72 (32%) were randomly assigned to a treatment group (24 to ibrutinib maintenance and 48 to treatment cessation). The remaining 153 patients were not randomly assigned and continued with ibrutinib monotherapy. Median follow-up of 208 patients still alive and not lost to follow-up at data cutoff on June 22, 2021, was 34·4 months (IQR 30·6-37·9). Progression-free survival after 12 months in the treatment cessation group was 98% (95% CI 89-100). Infections (in 130 [58%] of 225 patients), neutropenia (in 91 [40%] patients), and gastrointestinal adverse events (in 53 [24%] patients) were the most frequently reported; no new safety signals were detected. Serious adverse events were reported in 46 (40%) of 116 patients who were not randomly assigned and who continued ibrutinib maintenance after cycle 15, eight (33%) of 24 patients in the ibrutinib maintenance group, and four (8%) of 48 patients in the treatment cessation group. One patient who was not randomly assigned had a fatal adverse event (bleeding) deemed possibly related to ibrutinib. INTERPRETATION: These data point to a favourable benefit-risk profile of MRD-guided, time-limited treatment with ibrutinib plus venetoclax for patients with relapsed or refractory chronic lymphocytic leukaemia, suggesting that MRD-guided cessation and reinitiation is feasible in this patient population. FUNDING: AbbVie and Janssen.

Changes in Bcl-2 members after ibrutinib or venetoclax uncover functional hierarchy in determining resistance to venetoclax in CLL.

Chronic lymphocytic leukemia (CLL) cells cycle between lymph node (LN) and peripheral blood (PB) and display major shifts in Bcl-2 family members between those compartments. Specifically, Bcl-XL and Mcl-1, which are not targeted by the Bcl-2 inhibitor venetoclax, are increased in the LN. Because ibrutinib forces CLL cells out of the LN, we hypothesized that ibrutinib may thereby affect expression of Bcl-XL and Mcl-1 and sensitize CLL cells to venetoclax. We investigated expression of Bcl-2 family members in patients under ibrutinib or venetoclax treatment, combined with dissecting functional interactions of Bcl-2 family members, in an in vitro model of venetoclax resistance. In the PB, recent LN emigrants had higher Bcl-XL and Mcl-1 expression than did cells immigrating back to the LN. Under ibrutinib treatment, this distinction collapsed; significantly, the pretreatment profile reappeared in patients who relapsed on ibrutinib. However, in response to venetoclax, Bcl-2 members displayed an early increase, underlining the different modes of action of these 2 drugs. Profiling by BH3 mimetics was performed in CLL cells fully resistant to venetoclax due to CD40-mediated induction of Bcl-XL, Mcl-1, and Bfl-1. Several dual or triple combinations of BH3 mimetics were highly synergistic in restoring killing of CLL cells. Lastly, we demonstrated that proapoptotic Bim interacts with antiapoptotic Bcl-2 members in a sequential manner: Bcl-2 > Bcl-XL > Mcl-1 > Bfl-1. Combined, the data indicate that Bcl-XL is more important in venetoclax resistance than is Mcl-1 and provide biological rationale for potential synergy between ibrutinib and venetoclax.

[Environmental impact of prescribing in family medicine - Example of simple urinary tract infection]. / Impact environnemental de la prescription en médecine de famille - Exemple de l'infection urinaire simple.

As the pharmaceutical industry keeps growing, the presence and impact of drug residues in water is becoming increasingly well documented. These end up in wastewater after human consumption, and then in surface water if they are not sufficiently removed in wastewater treatment plants, harming aquatic organisms even in minute quantities. Antibiotics and NSAIDs are the most worrying for the environment. We would recommend here a reduction in their prescription in urinary tract infections, considering that spontaneous healing occurs in half of the cases. We indicate more natural alternatives, with a reasonable level of safety despite a low level of evidence.

L'industrie pharmaceutique ne cesse de croître, tandis que la présence et l'impact des résidus médicamenteux dans les eaux sont de mieux en mieux documentés. Ces derniers se retrouvent dans les eaux usées après leur consommation par l'homme, puis dans celles de surface en l'absence d'une élimination suffisante dans les stations d'épuration, nuisant aux organismes aquatiques, même en quantités infimes. Les antibiotiques et les AINS sont les plus préoccupants pour l'environnement. Nous proposons ici une stratégie de réduction de leur prescription dans l'infection urinaire, en tenant compte d'une guérison spontanée dans la moitié des cas. Nous indiquons des alternatives plus naturelles avec un niveau de sécurité raisonnable malgré un niveau de preuve faible.

[Integrative medicine: scientific literature in 2021]. / Médecine integrative - Littérature scientifique en 2021.

To illustrate the novelties in integrative and complementary medicine in 2021, the authors present a selection of six articles. One of them is specifically related to COVID-19. The other articles deal with themes that are always relevant and where complementary approaches represent a real added value. Two articles focus on low back pain, a common problem in primary care medicine. The others examine acupuncture in the oncological context, the use of therapeutic suggestions in an operative context, and Tai Chi. The authors thus provide an overview of the range of possible complementary therapeutic approaches that are increasingly supported by evidence, inviting them to be better integrated into clinical practice.

Pour illustrer les nouveautés en médecine intégrative et complémentaire en 2021, les auteur·e·s présentent une sélection de six articles. L'un s'intéresse plus spécifiquement au Covid-19. Les autres touchent des thématiques qui restent toujours d'actualité et où des approches complémentaires peuvent représenter une réelle plus-value. Deux articles ont pour thème les lombalgies, problématique courante en médecine de premier recours. Les autres examinent l'acupuncture dans le contexte oncologique, l'utilisation de suggestions thérapeutiques dans un contexte opératoire, et le Tai Chi. Les auteur·e·s donnent ainsi un aperçu de l'éventail d'approches thérapeutiques complémentaires possibles et de plus en plus soutenues par la science, invitant à les intégrer de mieux en mieux dans la pratique clinique.

[Scientific literature on integrative medicine in 2020]. / Littérature scientifique concernant la médecine intégrative en 202.

Scientific research in integrative medicine has undergone significant development in recent years. Several studies published in 2020 focus on the management of chronic pain. Hypnosis has been shown to be as effective in analgesia as cognitive-behavioral therapy and therapeutic education. A study on chronic low back pain showed lower health care costs for patients using complementary medicine. Furthermore, the hypothesis of super responders to acupuncture treatment does not seem to be confirmed. Yoga could be a useful approach in the prevention of migraines. With respect to the management of COVID-19, the addition of traditional Chinese medicine to conventional treatments could reduce a number of symptoms and the length of hospital stays, although the quality of data is limited.

La recherche en médecine intégrative connaît un développement important depuis quelques années. Plusieurs études publiées en 2020 concernent la prise en charge de la douleur chronique. L'hypnose s'est montrée aussi efficace contre la douleur que la thérapie cognitivo-comportementale et l'éducation thérapeutique. Une étude sur les lombalgies chroniques a indiqué des dépenses de santé plus basses pour les patients recourant aux médecines complémentaires. Par ailleurs, l'hypothèse de super-répondeurs à un traitement d'acupuncture ne semble pas se confirmer. Le yoga pourrait être une approche utile dans la prévention des migraines. En ce qui concerne la prise en charge du Covid-19, l'ajout de la médecine traditionnelle chinoise pourrait diminuer certains symptômes et la durée des hospitalisations, bien que la qualité des données reste limitée.

Satisfaction and experiences of patients taking fingolimod and involved in a pharmacy-based patient support program in Switzerland - a qualitative study.

BACKGROUND: Fingolimod is an oral multiple sclerosis drug that is considered a specialty drug due to its high cost and safety issues. The Fingolimod Patient Support Program (F-PSP) is a specialty pharmacy service developed to ensure the responsible use of fingolimod by promoting patient safety and medication adherence. This study aims to explore the satisfaction, experiences and perceptions regarding the F-PSP among patients currently involved in this program or recently withdrawn. METHODS: A qualitative study was conducted via individual, face-to-face semistructured interviews with patients involved in the F-PSP. The interviews were audio-recorded, transcribed verbatim, coded and analyzed via thematic content analysis. RESULTS: The main themes identified from the interviews (n = 17) were overall perception of the F-PSP, perception of the pharmacist-led consultations, perception of the tools (electronic monitor and drug intake graph), reasons to participate or potentially withdraw, and suggestions for improvements. Participants perceived the F-PSP as a reassuring support that complemented their medical care, providing a more human, personalized and person-centered approach than usual pharmacy care. Pharmacist-led consultations were valued for the medication-related and holistic support they provided. The importance of the pharmacist's attitude was emphasized. The electronic monitor was valued for promoting daily medication adherence and allowing the involvement of relatives, which reassured participants and their relatives. The participants appreciated the drug intake graph because it provided an objective overview of medication adherence, thereby reassuring, rewarding, and motivating them. The main reason to join the program was to be supported, especially with respect to medication adherence. CONCLUSIONS: Participants were satisfied with the F-PSP, each for different reasons. Their feedback enabled the identification of measures for the optimization of the F-PSP and should facilitate its dissemination and transfer to other drugs/diseases/populations. Essential elements of generic pharmacist-led patient support programs considered valuable from the patients' perspective were identified.

Procalcitonin and lung ultrasonography point-of-care testing to decide on antibiotic prescription in patients with lower respiratory tract infection in primary care: protocol of a pragmatic cluster randomized trial.

BACKGROUND: A minority of patients presenting with lower respiratory tract infection (LRTI) to their general practitioner (GP) have community-acquired pneumonia (CAP) and require antibiotic therapy. Identifying them is challenging, because of overlapping symptomatology and low diagnostic performance of chest X-ray. Procalcitonin (PCT) can be safely used to decide on antibiotic prescription in patients with LRTI. Lung ultrasound (LUS) is effective in detecting lung consolidation in pneumonia and might compensate for the lack of specificity of PCT. We hypothesize that combining PCT and LUS, available as point-of care tests (POCT), might reduce antibiotic prescription in LRTIs without impacting patient safety in the primary care setting. METHODS: This is a three-arm pragmatic cluster randomized controlled clinical trial. GPs are randomized either to PCT and LUS-guided antibiotic therapy or to PCT only-guided therapy or to usual care. Consecutive adult patients with an acute cough due to a respiratory infection will be screened and included if they present a clinical pneumonia as defined by European guidelines. Exclusion criteria are previous antibiotics for the current episode, working diagnosis of sinusitis, severe underlying lung disease, severe immunosuppression, hospital admission, pregnancy, inability to provide informed consent and unavailability of the GP. Patients will fill in a 28 day-symptom diary and will be contacted by phone on days 7 and 28. The primary outcome is the proportion of patients prescribed any antibiotic up to day 28. Secondary outcomes include clinical failure by day 7 (death, admission to hospital, absence of amelioration or worsening of relevant symptoms) and by day 28, duration of restricted daily activities, episode duration as defined by symptom score, number of medical visits, number of days with side effects due to antibiotics and a composite outcome combining death, admission to hospital and complications due to LRTI by day 28. An evaluation of the cost-effectiveness and of processes in the clinic using a mixed qualitative and quantitative approach will also be conducted. DISCUSSION: Our intervention targets only patients with clinically suspected CAP who have a higher pretest probability of definite pneumonia. The intervention will not substitute clinical assessment but completes it by introducing new easy-to-perform tests. TRIAL REGISTRATION: The study was registered on the 19th of June 2017 on the clinicaltrials.gov registry using reference number; NCT03191071 .

Agenda Setting During Follow-Up Encounters in a University Primary Care Outpatient Clinic.

At the beginning of the medical encounter, clinicians should elicit patients' agendas several times using open-ended questions. Little is known, however, about how many times physicians really solicit a patient's agenda during follow-up encounters. The objective was to analyze the number of agenda solicitations by physicians, of agendas initiated by physicians, and of patients' spontaneous agendas during the beginning and the entire encounter. We analyzed 68 videotaped follow-up encounters at a university primary care outpatient clinic. The number of different types of agenda setting was searched for and analyzed using negative binomial regression or logistic regression models. Physicians solicited agendas a mean ± SD of 0.8 ± 0.7 times/patient during the first 5 minutes and 1.7 ± 1.2 times/patient during the entire encounter. Physicians in 32.4% of encounters did not solicit the patient agenda, and there were never more than two physician's solicitations during the first 5 minutes. The mean number of physician's solicitations of the patients' agenda was 42% lower among female physicians during the first 5 minutes and 34% lower during the entire encounter. The number of agendas initiated by physicians was 1.2 ± 1.2/patient during the beginning and 3.2 ± 2.3/patient during the entire encounter. In 58.8% of the encounters, patients communicated their agendas spontaneously. There were twice as many patient spontaneous agendas (IRR = 2.12, p = .002) with female physicians than with males. This study showed that agenda solicitation with open-ended questions in follow-up encounters does not occur as often as recommended. There is thus a risk of missing new agendas or agendas that are important to the patient.

Chronic low back pain patients' use of, level of knowledge of and perceived benefits of complementary medicine: a cross-sectional study at an academic pain center.

BACKGROUND: Chronic pain patients often use complementary medicine (CM) to alleviate their pain; however, little is known about the use of CM by chronic low back pain (cLBP) patients. We investigated the frequency of use of CM by cLBP patients, the perceived effects of these therapies, patients' knowledge regarding CM, and patient-physician communication regarding CM. METHOD: A cross-sectional survey was conducted from November 2014 to February 2015. A questionnaire was distributed by physicians to 238 consecutive patients consulting for cLBP at the Pain Center of Lausanne University Hospital, Switzerland. Poisson regression model was used to analyze patients' level of knowledge regarding various CMs, and the logistic regression model was used to assess CM use for cLBP. RESULTS: The questionnaire was returned by 168 cLBP patients (response rate: 70.6%). Lifetime prevalence of CM use for cLBP was 77.3%. The most commonly used therapies were osteopathy (48.8%), massage (45.2%) and acupuncture (31.6%), rated for their usefulness on a 0-10 scale as a mean ± SD of 5.4 ± 2.7, 5.9 ± 2.5 and 3.8 ± 3.2, respectively. The CM treatment best known by patients was osteopathy, followed by massage and acupuncture. If their doctors proposed CM as a treatment for cLBP, 78% of participants reported being very or somewhat likely to try CM. Respondents with CM health insurance were more likely to use CM (OR = 2.26; 95%CI: 1.07-4.78; p = 0.031) for cLBP. Respondents having experienced cLBP for more than five years were more likely to use CM to treat their cLBP than respondents having experienced cLBP for one year or less (OR = 2.84; 95%CI: 1.02-7.88; p = 0.044). CONCLUSIONS: More than three-quarters of cLBP patients in our sample did use CM to treat their cLBP. The results showed that the most commonly used therapies were not necessarily the highest rated in terms of perceived usefulness. These results highlight the importance of developing integrative pain centers in which patients may obtain advice regarding CM treatments.

"It's the First Time I Feel as One". Patients' Experience of Therapeutic Body Wraps in Swiss Public Adult Inpatient Psychiatric Wards.

Many patients suffering from serious mental illness experience severe anxiety, and those with psychosis often report feeling that their bodies are falling apart. Expert opinions reported relational benefits and tranquilizing effects of therapeutic body wraps (TBWs). Yet this adjunct nursing therapy has rarely been studied and the existing knowledge is limited to single clinical cases reported from clinicians' perspectives. This study reports on seven adult patients, whose independent accounts of TBWs were audio-recorded, transcribed and cross-analyzed. It sheds light on a commonly underestimated need among many severely ill psychiatric patients to have their anxiety addressed on a bodily level.

[Insomnia: definitions, epidemiology and changes with age]. / Insomnie : définitions, épidémiologie et évolution avec l'âge.

INSOMNIA: DEFINITIONS, EPIDEMIOLOGY AND CHANGES WITH AGE. Chronic insomnia is a disorder defined as a subjective complaint relating to the quality and/or quantity of sleep associated with daytime impact, and which must be present 3 nights per week for a period of at least 3 months. This is a common sleep problem in the general population and represents a significant proportion of reasons for consultation in the general practice. It requires early identification at all ages of life to allow the establishment of adequate care, which will have the benefit of both improving the quality of life of these patients in the short term and preventing the consequences of chronic insomnia.

Rationale and design of a double-blinded, randomized placebo-controlled trial of 40 Hz light neurostimulation therapy for depression (FELIX).

BACKGROUND: Major depressive disorder (MDD) is a debilitating condition that affects more than 300 million people worldwide. Current treatments are based on a trial-and-error approach, and reliable biomarkers are needed for more informed and personalized treatment solutions. One of the potential biomarkers, gamma-frequency (30-80 Hz) brainwaves, are hypothesized to originate from the excitatory-inhibitory interaction between the pyramidal cells and interneurons. The imbalance between this interaction is described as a crucial pathological mechanism in neuropsychiatric conditions, including MDD, and the modulation of this pathological interaction has been investigated as a potential target. Previous studies attempted to induce gamma activity in the brain using rhythmic light and sound stimuli (GENUS - Gamma Entrainment Using Sensory stimuli) that resulted in neuroprotective effects in Alzheimer's disease (AD) patients and animal models. Here, we investigate the antidepressant, cognitive, and electrophysiological effects of the novel light therapy approach using 40 Hz masked flickering light for patients diagnosed with MDD. METHODS AND DESIGN: Sixty patients with a current diagnosis of a major depressive episode will be enrolled in a randomized, double-blinded, placebo-controlled trial. The active treatment group will receive 40 Hz masked flickering light stimulation while the control group will receive continuous light matched in color temperature and brightness. Patients in both groups will get daily light treatment in their own homes and will attend four follow-up visits to assess the symptoms of depression, including depression severity measured by Hamilton Depression Rating Scale (HAM-D17), cognitive function, quality of life and sleep, and electroencephalographic changes. The primary endpoint is the mean change from baseline to week 6 in depression severity (HAM-D6 subscale) between the groups.

Time-of-day-dependent variation of the human liver transcriptome and metabolome is disrupted in MASLD.

Background & Aims: Liver homeostasis is ensured in part by time-of-day-dependent processes, many of them being paced by the molecular circadian clock. Liver functions are compromised in metabolic dysfunction-associated steatotic liver disease (MASLD) and metabolic dysfunction-associated steatohepatitis (MASH), and clock disruption increases susceptibility to MASLD progression in rodent models. We therefore investigated whether the time-of-day-dependent transcriptome and metabolome are significantly altered in human steatotic and MASH livers. Methods: Liver biopsies, collected within an 8 h-window from a carefully phenotyped cohort of 290 patients and histologically diagnosed to be either normal, steatotic or MASH hepatic tissues, were analyzed by RNA sequencing and unbiased metabolomic approaches. Time-of-day-dependent gene expression patterns and metabolomes were identified and compared between histologically normal, steatotic and MASH livers. Results: Herein, we provide a first-of-its-kind report of a daytime-resolved human liver transcriptome-metabolome and associated alterations in MASLD. Transcriptomic analysis showed a robustness of core molecular clock components in steatotic and MASH livers. It also revealed stage-specific, time-of-day-dependent alterations of hundreds of transcripts involved in cell-to-cell communication, intracellular signaling and metabolism. Similarly, rhythmic amino acid and lipid metabolomes were affected in pathological livers. Both TNFα and PPARγ signaling were predicted as important contributors to altered rhythmicity. Conclusion: MASLD progression to MASH perturbs time-of-day-dependent processes in human livers, while the differential expression of core molecular clock components is maintained. Impact and implications: This work characterizes the rhythmic patterns of the transcriptome and metabolome in the human liver. Using a cohort of well-phenotyped patients (n = 290) for whom the time-of-day at biopsy collection was known, we show that time-of-day variations observed in histologically normal livers are gradually perturbed in liver steatosis and metabolic dysfunction-associated steatohepatitis. Importantly, these observations, albeit obtained across a restricted time window, provide further support for preclinical studies demonstrating alterations of rhythmic patterns in diseased livers. On a practical note, this study indicates the importance of considering time-of-day as a critical biological variable which may significantly affect data interpretation in animal and human studies of liver diseases.

Learning a Markov Logic network for supervised gene regulatory network inference.

BACKGROUND: Gene regulatory network inference remains a challenging problem in systems biology despite the numerous approaches that have been proposed. When substantial knowledge on a gene regulatory network is already available, supervised network inference is appropriate. Such a method builds a binary classifier able to assign a class (Regulation/No regulation) to an ordered pair of genes. Once learnt, the pairwise classifier can be used to predict new regulations. In this work, we explore the framework of Markov Logic Networks (MLN) that combine features of probabilistic graphical models with the expressivity of first-order logic rules. RESULTS: We propose to learn a Markov Logic network, e.g. a set of weighted rules that conclude on the predicate "regulates", starting from a known gene regulatory network involved in the switch proliferation/differentiation of keratinocyte cells, a set of experimental transcriptomic data and various descriptions of genes all encoded into first-order logic. As training data are unbalanced, we use asymmetric bagging to learn a set of MLNs. The prediction of a new regulation can then be obtained by averaging predictions of individual MLNs. As a side contribution, we propose three in silico tests to assess the performance of any pairwise classifier in various network inference tasks on real datasets. A first test consists of measuring the average performance on balanced edge prediction problem; a second one deals with the ability of the classifier, once enhanced by asymmetric bagging, to update a given network. Finally our main result concerns a third test that measures the ability of the method to predict regulations with a new set of genes. As expected, MLN, when provided with only numerical discretized gene expression data, does not perform as well as a pairwise SVM in terms of AUPR. However, when a more complete description of gene properties is provided by heterogeneous sources, MLN achieves the same performance as a black-box model such as a pairwise SVM while providing relevant insights on the predictions. CONCLUSIONS: The numerical studies show that MLN achieves very good predictive performance while opening the door to some interpretability of the decisions. Besides the ability to suggest new regulations, such an approach allows to cross-validate experimental data with existing knowledge.