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.

Reassessing the Chronic Lymphocytic Leukemia International Prognostic Index in the era of targeted therapies.

We evaluated the prognostic value of the Chronic Lymphocytic Leukemia International Prognostic Index (CLL-IPI) using a pooled dataset of CLL-patients treated first-line with targeted drugs (N=991) or chemoimmunotherapy (N=1,256). 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 (HR=3.296, 95%-CI 1.576-6.894, p=0.002), for high vs. intermediate (HR=1.365, 95%-CI 1.003-1.858, p=0.048), but not for very high vs. high. CLL-IPI factors ß2-microglobulin, IGHV mutational status, and TP53 status each retained prognostic value for PFS. The 3-year overall survival (OS)-rates by CLL-IPI risk group were 100%, 96%, 93.9%, and 89.4% 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%. 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) versus chemoimmunotherapy (N=812) across all risk groups, and OS-differences in all but low-risk patients were demonstrated. The CLL-IPI maintains its prognostic value in predicting PFS outcomes with targeted drugs. With the caveat of a short observation time 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. CLL2-BIG (NCT02345863), CLL2-BAG (NCT02401503), CLL2-BIO (NCT02689141), CLL2-BCG (NCT02445131), CLL2-GIVe (NCT02758665), CLL13 (NCT02950051), CLL14-trial (NCT02242942), CLL1 (NCT00262782), CLL8 (NCT00281918), and CLL11 (NCT01010061).

[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.

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.

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.

High-throughput Proteomics Identifies THEMIS2 as Independent Biomarker of Treatment-free Survival in Untreated CLL.

It remains challenging in chronic lymphocytic leukemia (CLL) to distinguish between patients with favorable and unfavorable time-to-first treatment (TTFT). Additionally, the downstream protein correlates of well-known molecular features of CLL are not always clear. To address this, we selected 40 CLL patients with TTFT ≤24 months and compared their B cell intracellular protein expression with 40 age- and sex-matched CLL patients with TTFT >24 months using mass spectrometry. In total, 3268 proteins were quantified in the cohort. Immunoglobulin heavy-chain variable (IGHV) mutational status and trisomy 12 were most impactful on the CLL proteome. Comparing cases to controls, 5 proteins were significantly upregulated, whereas 3 proteins were significantly downregulated. Of these, only THEMIS2, a signaling protein acting downstream of the B cell receptor, was significantly associated with TTFT, independently of IGHV and TP53 mutational status (hazard ratio, 2.49 [95% confidence interval, 1.62-3.84]; P < 0.001). This association was validated on the mRNA and protein level by quantitative polymerase chain reaction and ELISA, respectively. Analysis of 2 independently generated RNA sequencing and mass spectrometry datasets confirmed the association between THEMIS2 expression and clinical outcome. In conclusion, we present a comprehensive characterization of the proteome of untreated CLL and identify THEMIS2 expression as a putative biomarker of TTFT.

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.

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.

The Significance of Traditional and Complementary Medicine to Self-Care and Addressing Global Health Challenges: Advancing the Commitments of the Declaration of Astana Through a Strong Research Program.

The Declaration of Astana (DoA) developed at the Global Conference on Primary Health Care (PHC) in 2018 outlined a number of core commitments and aspirations that fall in line with the broader vision for advancing global health, addressing a number of health-related sustainable development goals and ultimately ensuring health for all. Two specific goals of the DoA that are of particular interest and concern to the argument posited here are as follows: "to build sustainable primary health care" and "to empower individuals and communities." Moreover, these specific goals and the broader declaration all point to and "highlight the importance of empowering individuals as self-carers." However, it would appear that the conception of PHC, the related health workforce and the types of self-care activities, practices and initiatives envisioned within the DoA fail to explicitly accommodate or fully acknowledge the importance of both traditional and complementary medicine (T&CM) and more specifically "T&CM self-care" in strengthening the health of all communities. The aim of this editorial is to help articulate the significance of T&CM to self-care and as a consequence to the success of the DoA and wider desired advances in global health.

Ibrutinib sensitizes CLL cells to venetoclax by interrupting TLR9-induced CD40 upregulation and protein translation.

Chronic lymphocytic leukemia (CLL) cells upregulate Bcl-2 proteins within the lymph node (LN) microenvironment. Signaling via B-cell receptor, Toll-like receptors and CD40 collectively reduce sensitivity to the BCL-2 inhibitor venetoclax. Time-limited treatment with venetoclax plus the BTK-inhibitor ibrutinib results in deep remissions, but how this combination affects LN-related signaling is not yet completely clear. Therefore, samples obtained from the HOVON141/VISION phase 2 clinical trial were used to analyze this. Two cycles of lead-in ibrutinib monotherapy resulted in decreased protein expression of Bcl-2 proteins in circulating CLL cells. Strikingly, at this timepoint CD40-induced venetoclax resistance was strongly attenuated, as was expression of CD40. Since CD40 signaling occurs within the CLL LN, we tested various LN-related signals that could affect CD40 signaling. While BCR stimulation had only a minor effect, TLR9 stimulation via CpG led to significantly increased CD40 expression and importantly, reverted the effects of ibrutinib treatment on venetoclax sensitivity by inducing overall protein translation. Together, these findings identify a novel effect of ibrutinib: interruption of TLR9-induced CD40 upregulation and translation of pro-survival proteins. This mechanism may potentially further inhibit priming of CLL cells in the LN microenvironment for venetoclax resistance.

JAK-STAT signalling shapes the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL.

Preventing or overcoming resistance to the Bcl-2 inhibitor venetoclax is an emerging unmet clinical need in patients with chronic lymphocytic leukaemia (CLL). The upregulation of anti-apoptotic Bcl-2 members through signalling pathways within the tumor microenvironment appears as a major factor leading to resistance to venetoclax. Previously, we reported that T cells can drive resistance through CD40 and non-canonical NF-κB activation and subsequent Bcl-XL induction. Moreover, the T cell-derived cytokines IL-21 and IL-4 differentially affect Bcl-XL expression and sensitivity to venetoclax via unknown mechanisms. Here, we mechanistically dissected how Bcl-XL is regulated in the context of JAK-STAT signalling in primary CLL. First, we demonstrated a clear antagonistic role of IL-21/STAT3 signalling in the NF-κB-mediated expression of Bcl-XL, whereas IL-4/STAT6 further promoted the expression of Bcl-XL. In comparison, Bfl-1, another NF-κB target, was not differentially affected by either cytokine. Second, STAT3 and STAT6 affected Bcl-XL transcription by binding to its promoter without disrupting the DNA-binding activity of NF-κB. Third, in situ proximity ligation assays (isPLAs) indicated crosstalk between JAK-STAT signalling and NF-κB, in which STAT3 inhibited canonical NF-κB by accelerating nuclear export, and STAT6 promoted non-canonical NF-κB. Finally, NF-κB inducing kinase (NIK) inhibition interrupted the NF-κB/STAT crosstalk and resensitized CLL cells to venetoclax. In conclusion, we uncovered distinct crosstalk mechanisms that shape the NF-κB response in CLL towards venetoclax sensitivity or resistance via Bcl-XL, thereby revealing new potential therapeutic targets.

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.

[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.

SARS-CoV-2 infection among employees working from home and on site: An occupational study in Switzerland.

During the COVID-19 pandemic, many companies implemented working from home to mitigate the spread of the disease among their employees. Using data from Corona Immunitas Nestlé, a seroepidemiological study conducted among employees from two Nestlé sites in Switzerland, we aimed to investigate whether there was a difference in SARS-CoV-2 infection rates between employees working most of the time from home and employees mobilized in a workplace equipped with a specialized occupational safety unit and strict sanitary measures. We also investigated whether this association was modified by household size, living with children, vulnerability, worries about an infection, and worries about adverse health consequences if infected. Data were collected between 8 December 2020, and 11 February 2021. Previous SARS-CoV-2 infections were ascertained by the presence of anti-SARS-CoV-2 IgG antibodies in the blood. Of the 425 employees included (53% women; mean age 42 years ranging between 21 and 64 years), 37% worked most of the time from home in 2020 and 16% had been infected with SARS-CoV-2. Participants who worked most of the time from home in 2020 had slightly higher odds of being infected with SARS-CoV-2 compared to participants who never or only sometimes worked from home (adjusted OR 1.29, 95% CI 0.73-2.27). The association was stronger in participants living alone or with one other person (adjusted OR 2.62, 95% CI 1.13-6.25). Among participants living with two or more other persons (adjusted OR 0.66, 95% CI 0.30-1.39) and among vulnerable participants (adjusted OR 0.53, 95% CI 0.13-1.93), working from home tended to be associated with lower odds of infection. In conclusion, in a context of strict sanitary measures implemented in the workplace, employees working from home did not seem to be at lower risk of infection compared to those working on site, especially if living alone or with one other person.

Practicing traditional Chinese medicine in the COVID-19 pandemic in Switzerland - an exploratory study.

BACKGROUND: To curb the spread of the first wave of the COVID-19 pandemic, the Swiss government declared a state of health emergency and ordered a legal restriction concerning the opening of healthcare institutions. In this study, we aimed to assess the proportion of traditional Chinese medicine (TCM) physicians and therapists who consulted patients regarding COVID-19 during the first wave of the pandemic in 2020 in Switzerland, as well as the extent to which COVID-19 affected their practices during the same period. METHODS: A retrospective study was performed by using a questionnaire from January to April 2021 among a random sample of TCM physicians and therapists based in Switzerland. The survey included questions on demographic characteristics, opening status of practices, channels of communication used for the medical encounter, and experience in managing the prevention, acute, and recovery stages of COVID-19 infection. RESULTS: Among the 320 participants, 76% consulted a patient regarding COVID-19 at least once. Overall, physicians and therapists consulted more patients during recovery (76.3%) and prevention (67.8%) than during the acute stage (19.8%) of the disease. Acupuncture was the most frequently used technique among TCM therapists and physicians consulting for prevention (80.4%) and recovery (92.5%), whereas Chinese pharmacopeia was the most used technique among those consulting for the acute stage (59.3%). Of those who closed their practices from March to April 2020 but kept consulting, telephone (30.4%) and home visits (29.9%) were the two principal methods of consultation. CONCLUSIONS: The restriction concerning the opening of practices induced a loss of the health workforce, especially among TCM therapists. Nonetheless, TCM therapists and physicians consulted patients regarding COVID-19, especially during the recovery stage. As there is a demand for the use of TCM in the context of COVID-19, it raises the need for a better consideration of TCM in the Swiss health care system.

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.

Preventing sexism and sexual harassment in medical schools by using Theater of the Oppressed as an interactive and reflexive tool.

OBJECTIVES: Among the measures taken to combat sexism and sexual harassment, prevention courses for medical students are one possibility. We aimed to describe the process of implementing a training course on the prevention of sexism and sexual harassment for medical students in two Swiss medical schools by using the Theater of the Oppressed as an interactive and reflexive tool within the course. The purpose of this theater was to give the students the opportunity to express themselves and to collectively look for and discuss ways to combat and escape from oppressive situations. RESULTS: This collaborative, innovative, and interactive implementation showed that different forms of a training course can be implemented with similar objectives in an adaptable and transferable manner. The interactive and reflexive Theater of the Oppressed was an appropriate option to reach the objectives. Courses were based on identifying and acting on concrete problematic situations by focusing on individual, collective, and institutional resources. Students reported a high level of satisfaction.

The impact of the COVID-19 pandemic on the continuity of care for at-risk patients in Swiss primary care settings: A mixed-methods study.

Continuity of care is important for the health of aging individuals with comorbidities. When initial coronavirus mitigation campaigns involved messaging such as "Stay at home-stay safe," and banned provision of non-urgent care, at-risk patients depending upon regular consultations with general practitioners (GPs) faced confusion about the possibility of seeking non-COVID-19 related healthcare. We employed a sequential explanatory mixed-methods design, consisting of a quantitative component followed by a qualitative component, to understand at-risk patients' health services use during the COVID-19 pandemic in Switzerland. Quantitatively, we used electronic medical records data from 272 GPs and 266,796 patients. Based on pre-pandemic data, we predicted weekly consultation counts as well as weekly measurement counts (blood pressure, glycated hemoglobin, and low-density lipoprotein cholesterol) per 100 patients that would be expected in 2020 in absence of a pandemic and compared those to actual observed values. Qualitatively, we conducted 23 semi-structured interviews with 24 GPs (∼45 min) and 37 interviews with at-risk patients (∼35 min). Quantitative results demonstrate a significant decrease in consultation and measurement counts during the first shutdown period, with consultation counts quickly returning to normal and moving within expected values for the rest of 2020. Qualitative data contextualize these findings with GPs describing constantly implementing material, administrative, and communication changes. GPs reported communication gaps with the authorities and noted a lack of clear guidelines delineating how to define "at-risk patients" and what cases were "urgent" to treat during shutdowns. Patient interviews show that patient-level factors, such as fear of contracting coronavirus, perceptions that GPs were overburdened, and a sense of solidarity, influenced patients' decisions to consult less at the beginning of the pandemic. Findings demonstrate communication gaps during pandemic periods and provide valuable lessons for future pandemic preparedness, particularly the need for contingency plans for the overall healthcare system instead of plans focusing only on the infectious agent itself.