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Abstract Background The discovery of the importance of the immune system and its role in oncogenesis led to the development of immunotherapy, a treatment that represents a major advance in oncology management. Due to the recent nature of immunotherapy, little is known about its side effects and their impact on quality of life. To date, there is no published study that accurately assesses the impact of immunotherapy on cognition, mood and/or fatigue in patients treated for cancer, despite potential neurological toxicities. The purpose of this study is to prospectively assess the incidence of cognitive impairment and cognitive complaints among cancer patients naïve for immunotherapy without concomitant anti-cancer treatment. Methods The Cog-Immuno trial is a multicentre longitudinal study addressing patients with cancer candidate to receive immunotherapy alone (n = 100). Immunotherapy treatment will include either anti-PD1/PDL1 or anti-CTLA4 monotherapy or combination therapy. Cognitive and quality of life assessment, electrocardiogram (ECG) and biological tests will be performed at baseline, thereafter 3, and 6 months after immunotherapy initiation. The primary endpoint is the proportion of patients treated by immunotherapy who will experience a decline in cognitive performances or in Montreal Cognitive Assessment (MoCA) score within 3 months after inclusion. Secondary endpoints concern: anxiety, depression, fatigue, clinical characteristics, biological data and neurophysiological measures (heart rate variability and hemispheric lateralization). A pre-clinical study will be conducted in cancer bearing mice receiving checkpoint inhibitors (ICI) with the evaluation of cognitive functions and emotional reactivity, collection of blood samples and investigation of neurobiological mechanisms from brain slices. Discussion Assessing and understanding the incidence and the severity of cognitive impairment and its impact on quality of life in cancer patients treated by immunotherapy is a major issue. The results of this study will provide information on the impact of these treatments on cognitive functions in order to help the physicians in the choice of the treatment. Trial registration NCT03599830, registered July 26, 2018. Protocol version Version 5.1 dated from 2020/10/02.

Objective: Myocardial infarction (MI) results in mental health consequences, including depression and post-traumatic stress disorder (PTSD). The risk and protective factors of such mental consequences are not fully understood. This study examined the relation between MI severity and future mental health consequences and the moderating role of vagal nerve activity. Methods: In a reanalysis of data from the Myocardial Infarction-Stress Prevention Intervention (MI-SPRINT) study, 154 post-MI patients participated. MI severity was measured by the Killip Scale and by troponin levels. Depression and PTSD symptoms were assessed with valid questionnaires, both at 3 and 12 months. Vagal nerve activity was indexed by the heart rate variability (HRV) parameter of the root-mean square of successive R-R differences (RMSSD). Following multivariate analyses, the association between MI severity and distress was examined in patients with low and high HRV (RMSSD = 30 ms). Results: In the full sample, the Killip index predicted post-MI distress only at 3 months, while troponin predicted distress at 3- and 12-months post-MI. However, HRV moderated the effects of the Killip classification; Killip significantly predicted symptoms of depression and PTSD at 3- and 12-months post-MI, but only in patients with low HRV. Such moderation was absent for troponin. Conclusion: MI severity (Killip classification) predicted post-MI depression and PTSD symptoms, but only in patients with low HRV, suggesting that the vagal nerve is a partial protective (moderating) factor in the relation between Killip score and post-MI distress.

BackgroundInfective endocarditis (IE) is a disease that poses a serious health risk. It is important to identify high-risk patients early in the course of their treatment. In the current study, we evaluated the prognostic value of ultra-short heart-rate variability (HRV), an index of vagal nerve activity, in IE.MethodsRetrospective analysis was performed on adult patients admitted to a tertiary hospital due to IE. A logistic regression (LR) was used to determine whether clinical, laboratory, and HRV parameters were predictive of specific clinical features (valve type, staphylococcal infection) or severe short-term complications (cardiac, metastatic infection, and death). The accuracy of the model was evaluated through the measurement of the area under the curve (AUC) of the receiver operating characteristic curve (ROC). An analysis of survival was conducted using Cox regression. A number of HRV indices were calculated, including the standard deviation of normal heart-beat intervals (SDNN) and the root mean square of successive differences (RMSSD).Results75 patients, aged 60.3(±18.6) years old, were examined. When compared with published age- and gender-adjusted HRV norms, SDNN and RMSSD were found to be relatively low in our cohort (75%-76% lower than the median; 33%-41% lower than the 2nd percentile). 26(34.6%) patients developed a metastatic infection, with RMSSDConclusionSDNN, and particularly RMSSD, derived from ultra-short ECG recordings, may provide prognostic information about patients presenting with IE.

ObjectiveIdentifying new modifiable prognostic markers is important for ovarian cancer (OC). Low parasympathic activity is associated with inflammation, oxidative stress and sympathetic nervous system activation. Previous studies reported that low vagal nerve activity, measured by low heart rate variability (HRV), may predict poor cancer prognosis. We aimed to examine the prognostic value of HRV in OC.MethodsThis bicentric retrospective study included patients diagnosed with serous OC FIGO stage ≥IIB, between January 2015 and August 2019, with electrocardiograms (ECG) available around diagnosis. HRV was measured from ECG using the time domain parameter of standard deviation of all normal-to-normal heartbeat intervals (SDNN). Optimal SDNN cut-off was determined using the Youden index criteria of time-dependent ROC curves. We used multivariate cox proportional hazard models to investigate the association between HRV and overall survival (OS), while adjusting for well-known OC prognostic factors.ResultsThe 202 patients included were 65.7 years-old on average, 93% had stage FIGO IIIC/IV, 56% had complete surgical resection. Median OS was 38.6 months [95%CI:34.4-47.4]. The median SDNN was 11.1ms, with an optimal cut-off of 10ms to predict OS. OS was shorter for patients with low HRV compared to high HRV (26.4 vs 45.1 months; p

Type 2 diabetic mellitus (T2DM) is a common chronic disease and a substantial risk factor of other fatal illnesses. At its core is insulin resistance, where chronic low-level inflammation is among its main causes. Thus, it is crucial to modulate this inflammation. This review paper provides scientific neuroimmunological evidence on the protective roles of the vagal nerve in T2DM. First, the vagus inhibits inflammation in a reflexive manner via neuroendocrine and neuroimmunological routes. This may also occur at the level of brain networks. Second, studies have shown that vagal activity, as indexed by heart-rate variability (HRV), is inversely related to diabetes and that low HRV is a predictor of T2DM. Finally, some emerging evidence shows that vagal nerve activation may reduce biomarkers and processes related to diabetes. Future randomized controlled trials are needed to test the effects of vagal nerve activation on T2DM and its underlying anti-inflammatory mechanisms.

Thousands of migrants passed through the Balkans whilst migrating from the Middle East to Europe between 2015 and 2016. Humanitarian actions were conducted throughout this route as agencies and governments provided support. The Camp of Preševo, on the Southern border of Serbia, was established by the local authorities as a registration camp to monitor the migration and deliver aid. Part of this aid was psychosocial. Past studies show a relatively high prevalence of stress symptoms among forced migrants, presumably due to exposure to war-related atrocities and experience of forced migration. NATAN, an Israeli non-governmental organisation, is a volunteer-based organisation that delivered psychosocial support to the migrants using the ‘SIX Cs model’. This model focuses on cognitive and behavioural components and is based on the neuropsychology of resilience. It has advantages that were relevant to the context of the camp, namely culturally adaptive, easy to administer, short and adjustable to varied contexts. Moreover, the model gives tools, which could be used later by the migrants in the absence of a therapist. This report describes the SIX Cs model and the implementation of its intervention in the Preševo camp.

The combination of radiotherapy (RT) with immunotherapy represents a promising treatment modality for non-small cell lung cancer (NSCLC) patients. As only a minority of patients shows a persistent response today, a spacious optimization window remains to be explored. Previously we showed that fractionated RT can induce a local immunosuppressive profile. Based on the evolving concept of an immunomodulatory role for vagal nerve stimulation (VNS), we tested its therapeutic and immunological effects alone and in combination with fractionated RT in a preclinical-translational study. Lewis lung carcinoma-bearing C57Bl/6 mice were treated with VNS, fractionated RT or the combination while a patient cohort with locally advanced NSCLC receiving concurrent radiochemotherapy (ccRTCT) was enrolled in a clinical trial to receive either sham or effective VNS daily during their 6 weeks of ccRTCT treatment. Preclinically, VNS alone or with RT showed no therapeutic effect yet VNS alone significantly enhanced the activation profile of intratumoral CD8+ T cells by upregulating their IFN-γ and CD137 expression. In the periphery, VNS reduced the RT-mediated rise of splenic, but not blood-derived, regulatory T cells (Treg) and monocytes. In accordance, the serological levels of protumoral CXCL5 next to two Treg-attracting chemokines CCL1 and CCL22 were reduced upon VNS monotherapy. In line with our preclinical findings on the lack of immunological changes in blood circulating immune cells upon VNS, immune monitoring of the peripheral blood of VNS treated NSCLC patients (n=7) did not show any significant changes compared to ccRTCT alone. As our preclinical data do suggest that VNS intensifies the stimulatory profile of the tumor infiltrated CD8+ T cells, this favors further research into non-invasive VNS to optimize current response rates to RT-immunotherapy in lung cancer patients.

In response to adverse social-environmental conditions, leukocytes gene expression profile is altered in a pattern recognized as the conserved transcriptional response to adversity (CTRA). This entails the up-regulated expression of pro-inflammatory genes and down-regulated expression of genes involved in type-I interferon (IFN) related anti-viral immunity. In contrast, vagal nerve activity is recognized as a significant anti-inflammatory modulator. In this work, we investigated the association between CTRA and vagal activity indicated by the standard deviation of all NN interval (SDNN), a measure of heart-rate variability, in breast cancer patients awaiting surgery (n = 16). This association was tested both at the molecular leukocyte transcription factor activity level, as well as at the cytokines serum levels. We found an association between higher SDNN and increased interferon (IFN) related anti-viral pathways, both on the leukocyte transcription factor level and serum protein level. Unexpectedly, we also found a positive correlation between higher SDNN and pro-inflammatory transcription factor activity and cytokine serum level, potentially suggesting that increased vagal activity was induced by increased inflammation, in the context of pre-surgical stress and the presence of malignant tissue. Transcription origin analysis (TOA) suggests a role for monocyte and B-cells in the anti-inflammatory and anti-metastatic effects induced by vagal nerve signaling. Larger prospective studies are needed to verify and elaborate on the results from this small cross-sectional study.

Objective: An effective method for preventing the Human Immunodeficiency Virus (HIV) is condom use. Yet, research shows limited effects of education on increasing condom use. This research examined the effects of psychological inoculation (PI) versus education on condom use -barriers and –tendencies, using a fully automatized online system. Design: Two randomized controlled trials. In Study 1, 59 Sub-Saharan students were included while Study 2 20 European students were included. In both studies, participants were randomly assigned to PI or control conditions. In Study 2, we additionally matched pairs on gender and condom barriers. In the PI, participants received challenging sentences they had to refute. Main outcome measures: An indirect condom use test (I-CUTE) and a condom use barriers questionnaire, assessed at baseline and a month later. Results: In Study 1, a significant increase in I-CUTE scores and no change in barriers was found in the PI condition. Controls did not change on either outcome. In Study 2, two sub-scales of condom barriers (concerning partner and satisfaction) were significantly decreased in the PI group, while in controls, barriers significantly increased over time. In both groups, I-CUTE scores tended to increase. Conclusions: These results replicate previous studies and extend them to a fully automatized system without counselors.

Background Patients with COVID-19 present with a variety of clinical manifestations, ranging from mild or asymptomatic disease to severe illness and death. Whilst previous studies have clarified these and several other aspects of COVID-19, one of the ongoing challenges regarding COVID-19 is to determine which patients are at risk of adverse outcomes of COVID-19 infection. It is hypothesized that this is the result of insufficient inhibition of the immune response, with the vagus nerve being an important neuro-immuno-modulator of inflammation. Vagus nerve activity can be non-invasively indexed by heart-rate-variability (HRV). Therefore, we aimed to assess the prognostic value of HRV, as a surrogate marker for vagus nerve activity, in predicting mortality and intensive care unit (ICU) referral, in patients hospitalized with COVID-19. Methods A retrospective cohort study including all consecutive patients (n = 271) diagnosed and hospitalized with COVID-19 between March 2020 and May 2020, without a history of cardiac arrhythmias (including atrial and ventricular premature contractions), pacemaker, or current bradycardia (heart rate 110 bpm). HRV was based on one 10s ECG recorded at admission. 3-week survival and ICU referral were examined. Results HRV indexed as standard deviation of normal to normal heartbeat intervals (SDNN) predicted survival (H.R. = 0.53 95%CI: 0.31–0.92). This protective role was observed only in patients aged 70 years and older, not in younger patients. HRV below median value also predicted ICU referral within the first week of hospitalization (H.R = 0.51, 95%CI: 0.29–0.90, P = 0.021). Conclusion Higher HRV predicts greater chances of survival, especially in patients aged 70 years and older with COVID-19, independent of major prognostic factors. Low HRV predicts ICU indication and admission in the first week after hospitalization.

Abstract Thousands of migrants arrived in Europe via the Balkan route, many with various health conditions. The camp of Preševo, Serbia, close to the Macedonian border, was established by the Serbian government and run by the United Nations High Commissioner. The camp was wstablished for Refugees (UNHCR) late in 2015 as a registration and a transfer camp for refugees traveling through the Balkans on their way from the Near East to Western Europe. Refugees stayed at the camp for several hours or a day. NATAN, an Israeli non-governmental volunteer organization, in collaboration with HUMEDICA, a German organization, established a clinic at the camp, staffed by Israeli and German personnel. The Israeli team consisted of a doctor, nurse, and social worker, at least one of whom spoke Arabic. The language barrier was bridged through the fact that Arabic is commonly spoken in Israel, and more than half of the volunteers were Palestinian-Israelis. As for the Farsi language, we were helped by interpreters from the Department of Languages in the University of Belgrade. This report contains data on 2136 consecutive clients visiting the clinic between December 2015 and February 2016. The report focuses on the three most frequent major countries of origin, Syria (51%), Iraq (18%), and Afghanistan (31%). Analysis of the age distribution revealed that 36% were under 18 years of age, while only 5% were above the age of 60. Male gender was predominant. Infections were the most common diagnosis (61%) followed by pain in various body parts (13%). Antibiotics were prescribed in 47.6% of the infections. Most of the visits were for minor illnesses, with very few cases of chronic diseases such as diabetes (28 visits) or hypertension (17 visits). We provide the demographic correlates of migrants’ health conditions and discuss the findings in light of past studies and the context of the present sample of migrants.

One of the challenges facing researchers in the domain of human immunodeficiency virus prevention is the assessment of condom use in an unbiased self-reported manner. The current study presents the development and preliminary validation of an indirect condom use test (I-CUTE), designed to assess condom use tendencies and to overcome self-report biases. Two samples were included using correlational designs. In sample 1, 88 students from European university completed the I-CUTE with questionnaires of condom use barriers, social desirability, and condom use negotiation self-efficacy. In sample 2, 212 students from sub-Saharan universities completed the I-CUTE with questionnaires of condom use barriers and knowledge. The I-CUTE included 17 pictures of human figures in relation to condom use, where participants had to choose one of the four a-priori given sentences reflecting the figures’ thoughts. This represented a semi-projective, yet standardized test. In sample 1, I-CUTE scores were inversely related to barriers, positively correlated with condom use negotiation self-efficacy and unrelated to social desirability. In sample 2, I-CUTE scores were inversely related to barriers and unrelated to knowledge scores. In a multiple regression, condom use barriers had a unique contribution to explaining variance in I-CUTE scores, beyond the contribution of background variables and knowledge. These results support the preliminary reliability and validity of the I-CUTE tool in a variety of cultures, and reveal its lack of bias by social desirability and the importance of condom use barriers in condom use tendencies.

Background Health education alone has a limited impact on HIV prevention programs, possibly because it does not systematically target social and cognitive factors that affect condom use. Objectives To systematically evaluate the effectiveness and methodological quality of HIV prevention interventions, which targeted factors related to social cognitive models (SCM) in the Sub-Saharan context. Method Ten online databases were searched using prespecified terms. Data extraction and quality assessment (on a 0–8 scale) were carried out and study results were critically described. Results Eight studies meeting the inclusion criteria were identified and reviewed. Three interventions showed significant effects on condom use. The most targeted SCM factors were communication skills and self-efficacy. The average methodological quality score was 5.75. Conclusion There is a need to use other intervention methods targeting SCM determinants of condom use and to improve the quality of the assessment tools, to increase condom use towards HIV prevention.

Background: The wave of terrorist attacks over the past years in Europe and other regions may cause problems such as anxiety and depressive symptoms. Some studies suggest that perceived threat might also trigger physical health problems. Objective: To investigate the association between feeling threatened and subjective health during the week following a terrorist attack. Method: Online survey with a self-selected sample in the Belgian population one week after the terrorist attacks in 2016. Participants were invited through the Belgian media to fill in a questionnaire in Dutch, French or English on a website. The main outcomes were the association between ‘feeling threatened’ and subjective health problems. Perceived threat was measured with the question ‘During the week after the attacks … Did you feel threatened?’ Subjective health was measured by using standardized scales (ACSA, PHQ-4, PHQ-15). Results: A total of 2620 respondents completed the questionnaire, of whom 69.8% were female, 27.7% lived and 43.1% worked in Brussels. Gender, age, place of living and working, media exposure, religiousness and religious affiliation were associated significantly with higher perceived threat. A total of 21% of the respondents felt much or very much threatened during the week after the attacks. They reported significantly higher levels of mental and physical health problems. The most frequently reported problems were anxiety and depressive symptoms. The health problems that differentiated most markedly between those with low and high levels of perceived threat were fainting spells, chest pain and shortness of breath. Conclusion: In a self-selected sample of respondents, ‘feeling threatened’ was strongly associated with lower level of wellbeing and higher levels of mental and physical health problems. The most prevalent health problems were mental health problems but the most pronounced differences between people with low versus high levels of perceived threat were physical health problems.

Today, more and more problems that scientists need to tackle are complex problems. Many examples of these can be found in the health sciences, medicine and ecology. Typical features of complex problems are that they cannot be studied by one discipline and that they need to take into account subjective data as well as objective data. Two promising responses to deal with complex problems are Transdisciplinary and Mixed Method approaches. However, there is still a lacuna to fill, with transdisciplinary studies bridging the social sciences and biomedical sciences. More specifically, we need more and better studies that combine qualitative data about subjective experiences, perception and so on with objective, quantitative, neurophysiological data. We believe that the combination of qualitative and neurophysiological data is a good example of what we would like to call transdisciplinary mixed methods. In this article, we aim to explore the opportunities of transdisciplinary mixed-methods studies in which qualitative and neurophysiological data are used. We give a brief overview of what is characteristic for this kind of studies and illustrate this with examples; we point out strengths and limitations and propose an agenda for the future. We conclude that transdisciplinary mixed-methods studies in which qualitative and neurophysiological data are used have the potential to improve our knowledge about complex problems. A main obstacle seems to be that most scientists from the biomedical sciences are not familiar with the (qualitative) methods from the social sciences and vice versa. To end this ‘clash of paradigms’™, we urgently need to cultivate transdisciplinary thinking.

Past studies have shown that in attempts to prevent HIV, health education yields little change in condom use. The reason may be that education fails to target barriers for changing behaviour. The present controlled pilot study tested whether psychological inoculation (PI) reduces such barriers for using male condoms. Twenty-two Nigerian women with HIV were randomly assigned to receive PI or health education (control). In the PI condition, women learned to refute sentences reflecting barriers against condom use, while controls learned how to use condoms and the consequences of their non-use. Barriers for condom use, self-efficacy to negotiate condom use with partners and actual condom use were self-reported before and one week after interventions. Results revealed that only in the PI group were there statistically significant increases in condom use negotiating self-efficacy and reductions in barriers concerning motivation, sexual satisfaction and partners. Controls reported no statistically significant changes. However, actual reported condom use was unchanged in both groups. Thus, it is feasible to conduct PI interventions in an African sample of HIV patients. Furthermore, PI can reduce cognitive barriers for condom use, while health education yields little changes in such outcomes over time. If replicated in larger samples with longer follow-ups, these findings could eventually have implications for HIV prevention in several world regions.

Background: Following the earthquake of August 2021 in Haiti, humanitarian agencies provided support to the local population. NATAN, a voluntary based non-governmental organization, had arrived in the field five days after the earthquake and provided medical support based on a mobile clinic in seven villages close to the epicenter of the earthquake. Methods: We conducted a cross-sectional study on data collected from 331 persons of concern, as part of ‘good clinical practice’. They received basic treatment such as antibiotics and minor surgical interventions following a diagnosis. The main variables that were collected in this intervention included demographic data, main diagnoses, and main treatments. We also examined the distance from the earthquake epicenter (DfE) and its effects on the diagnoses and treatments. Results: Several interesting findings were observed. A significant association between the DfE and the diagnoses was found, where within the group closest to the epicenter, the most prevalent diagnosis was internal medicine problems (40.3%). Conclusions: It is possible that since five days had passed since the earthquake, the expected diagnoses of traumatic injuries were reduced, leaving sub-acute problems to be diagnosed and treated. Finally, mental health symptoms and stress levels should be assessed systematically and with validated measures.