Direct and indirect impact of SARS-CoV-2 on the brain.

Although COVID-19 is mostly a pulmonary disease, it is now well accepted that it can cause a much broader spectrum of signs and symptoms and affect many other organs and tissue. From mild anosmia to severe ischemic stroke, the impact of SARS-CoV-2 on the central nervous system is still a great challenge to scientists and health care practitioners. Besides the acute and severe neurological problems described, as encephalopathies, leptomeningitis, and stroke, after 2 years of pandemic, the chronic impact observed during long-COVID or the post-acute sequelae of COVID-19 (PASC) greatly intrigues scientists worldwide. Strikingly, even asymptomatic, and mild diseased patients may evolve with important neurological and psychiatric symptoms, as confusion, memory loss, cognitive decline, chronic fatigue, associated or not with anxiety and depression. Thus, the knowledge on the correlation between COVID-19 and the central nervous system is of great relevance. In this sense, here we discuss some important mechanisms obtained from in vitro and in vivo investigation regarding how SARS-CoV-2 impacts the brain and its cells and function.

Acute TNFα levels predict cognitive impairment 6-9 months after COVID-19 infection.

BACKGROUND: A neurocognitive phenotype of post-COVID-19 infection has recently been described that is characterized by a lack of awareness of memory impairment (i.e., anosognosia), altered functional connectivity in the brain's default mode and limbic networks, and an elevated monocyte count. However, the relationship between these cognitive and brain functional connectivity alterations in the chronic phase with the level of cytokines during the acute phase has yet to be identified. AIM: Determine whether acute cytokine type and levels is associated with anosognosia and functional patterns of brain connectivity 6-9 months after infection. METHODS: We analyzed the predictive value of the concentration of acute cytokines (IL-1RA, IL-1ß, IL-6, IL-8, IFNγ, G-CSF, GM-CSF) (cytokine panel by multiplex immunoassay) in the plasma of 39 patients (mean age 59 yrs, 38-78) in relation to their anosognosia scores for memory deficits via stepwise linear regression. Then, associations between the different cytokines and brain functional connectivity patterns were analyzed by MRI and multivariate partial least squares correlations for the whole group. RESULTS: Stepwise regression modeling allowed us to show that acute TNFα levels predicted (R2 = 0.145; ß = -0.38; p = .017) and were associated (r = -0.587; p < .001) with scores of anosognosia for memory deficits observed 6-9 months post-infection. Finally, high TNFα levels were associated with hippocampal, temporal pole, accumbens nucleus, amygdala, and cerebellum connectivity. CONCLUSION: Increased plasma TNFα levels in the acute phase of COVID-19 predict the presence of long-term anosognosia scores and changes in limbic system functional connectivity.

Frequency of Abnormally Low Neuropsychological Scores in Post-COVID-19 Syndrome: the Geneva COVID-COG Cohort.

OBJECTIVE: Several studies have reported poor long-term neuropsychological performances in patients following severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, but none has yet considered the effect of administering multiple intercorrelated neuropsychological tests and assessed the frequency of cognitive deficits in a normative population. Our aim was therefore to assess the presence of cumulative neuropsychological deficits in an actual post-coronavirus disease of 2019 (COVID-19) comparison group versus one simulated using Monte-Carlo methods. METHOD: Validated neuropsychological Monte-Carlo simulation methods were applied to scores from a battery of neuropsychological tests (memory, executive, attentional, perceptual, logical reasoning, language, and ideomotor praxis) administered to 121 patients who had had mild, moderate, or severe COVID-19 (mean age: 56.70 years; 32% women), 222 ± 43 days post-infection. The cumulative percentages of the three severity subgroups were compared with the results of a false discovery rate-corrected probability analysis based on normative data. RESULTS: The cumulative percentages of deficits in memory and executive functions among the severe and moderate patients were significantly higher than those estimated for the normative population. Moderate patients also had significantly more deficits in perception and logical reasoning. In contrast, the mild group did not have significantly more cumulative deficits. CONCLUSIONS: Moderate and severe forms of COVID-19 cause greater long-term neuropsychological deficits than those that would be found in a normative population, reinforcing the hypothesis of long-term effects of SARS-CoV-2 on cognitive function, independent of the severity of the initial infection.

Monocytosis in the acute phase of SARS-CoV-2 infection predicts the presence of anosognosia for cognitive deficits in the chronic phase.

Reduced awareness of neuropsychological disorders (i.e., anosognosia) is a striking symptom of post-COVID-19 condition. Some leukocyte markers in the acute phase may predict the presence of anosognosia in the chronic phase, but they have not yet been identified. This study aimed to determine whether patients with anosognosia for their memory deficits in the chronic phase presented specific leukocyte distribution in the acute phase, and if so, whether these leukocyte levels might be predictive of anosognosia. First, we compared the acute immunological data (i.e., white blood cell differentiation count) of 20 patients who displayed anosognosia 6-9 months after being infected with SARS-CoV-2 (230.25 ± 46.65 days) versus 41 patients infected with SARS-Cov-2 who did not develop anosognosia. Second, we performed an ROC analysis to evaluate the predictive value of the leukocyte markers that emerged from this comparison. Blood circulating monocytes (%) in the acute phase of SARS-CoV-2 infection were associated with long-term post-COVID-19 anosognosia. A monocyte percentage of 7.35% of the total number of leukocytes at admission seemed to predict the presence of chronic anosognosia 6-9 months after infection.

[Impact of the COVID-19 Outbreak on the management of patients with gynecological cancers]. / Impact de la pandémie de Covid-19 sur les modifications thérapeutiques des patientes atteintes de cancers gynécologiques.

OBJECTIVE: The exceptional health situation related to the SARS-Cov2 coronavirus pandemic (COVID-19) required a deep and very quickly adaptation of management practices in gynecological cancer. The main objective is to estimate the proportion of patients with treatment modifications. METHOD: This is a multicenter prospective study conducted in 3 university gynecological cancer departments (HCLyon, France) during the period of confinement (March 16 to May 11, 2020). All patients with non-metastatic breast cancer or gynecological cancer were included. The planned treatment, postponement, delay and organizational modifications (RCP, teleconsultations) were studied. RESULTS: Two hundred and five consecutive patients were included, average age 60.5±1.0. 7 patients (3.4%) had SARS-Cov-2 infection, 2 patients died. One hundred and twenty-two patients (59.5%) had a treatment maintained, 72 patients (35.1%) postponed, 11 patients (5.4%) cancelled. Of the 115 (56.1%) planned surgeries, 40 (34.8%) postponed, 7 cancelled (6.1%). 9 patients (7.8%) had a surgical modification. Of the 59 (28.8%) radiotherapy treatments scheduled, 24 (40.7%) postponed and 2 (3.4%) cancelled. Of the 56 (27.3%) chemotherapy treatment planned, 8 (14.3%) postponed and 2 (3.6%) cancelled. One hundred and forty-five patients (70.7%) have been discussed in multidisciplinary meeting. One hundred and fifty-eight patients (77%) had a teleconsultation system. CONCLUSION: Our study assessed the impact of the COVID-19 pandemic on therapeutic management of patients with gynecological cancer during the period of confinement. This will probably improve our management of an eventual epidemic rebound or future health crisis.

Neuroinflammation at single cell level: What is new?

Multiple sclerosis is a chronic and demyelinating disease of the central nervous system (CNS), most prevalent in women, and with an important social and economic cost worldwide. It is triggered by self-reacting lymphocytes that infiltrate the CNS and initiate neuroinflammation. Further, axonal loss and neuronal death takes place, leading to neurodegeneration and brain atrophy. The murine model for studying MS, experimental autoimmune encephalomyelitis (EAE), consists in immunizing mice with myelin-derived epitopes. APCs activate encephalitogenic T CD4 and CD8 lymphocytes that migrate mainly to the spinal cord resulting in neuroinflammation. Most of the knowledge on the pathophysiology and treatment of MS was obtained from EAE experiments, as Th17 cells, anti-alpha4 blocking Abs and the role of microbiota. Conversely, recent technology breakthroughs, such as CyTOF and single-cell RNA-seq, promise to revolutionize our understanding on the mechanisms involved both in MS and EAE. In fact, the importance of specific cellular populations and key molecules in MS/EAE is a constant matter of debate. It is well accepted that both Th1 and Th17 T CD4 lymphocytes play a relevant role in disease initiation after re-activation in situ. What is still under constant investigation, however, is the plasticity of the lymphocyte population, and the individual contribution of both resident and inflammatory cells for the progression or recovery of the disease. Thus, in this review, new findings obtained after single-cell analysis of blood and central nervous system infiltrating cells from MS/EAE and how they have contributed to a better knowledge on the cellular and molecular mechanisms of neuroinflammation are discussed.

COVID-19 Pandemic and Dysbiosis: Can the Ivermectin Hysteria Lead to an Increase of Autoimmune Neuroinflammatory Diseases?

The pandemic caused by the SARS-CoV-2 has made new treatments a goal for the scientific community. One of these treatments is Ivermectin. Here we discuss the hypothesis of dysbiosis caused by the use of Ivermectin and the possible impacts on neuroinflammatory diseases after the end of the pandemic.

Interventions Developed with the Intervention Mapping Protocol in Work Disability Prevention: A Systematic Review of the Literature.

Purposes Intervention mapping (IM) is a protocol for developing effective behavior change interventions. It has been used for 10 years to develop work disability prevention (WDP) interventions, but it is not known to what extent and with what success. The main objective of this study was to review the effectiveness of these interventions. Secondary objectives were to review their fidelity to the IM protocol, their theoretical frameworks and their content. Methods A search strategy was conducted in MEDLINE, Web of Science, PsycINFO, Pascal, Francis, and BDSP. All titles and abstracts were reviewed. A standardized extraction form was developed. All included studies were reviewed by two reviewers blinded to each other. Results Eight WDP interventions were identified aimed at return to work (RTW; n = 6) and self-management at work (n = 2). RTW interventions targeted workers with stress-related mental disorders (n = 1), low back pain (n = 1), musculoskeletal disorders (n = 1), cancer (n = 2) and gynecological surgery (n = 1). The fidelity to the IM protocol was weaker for the participatory planning group. Matrices of change, change methods, and applications were systematically reported. The main theoretical frameworks used were the attitude-social influence-self efficacy model (n = 4) and the theory of planned behavior (n = 2). Half of the interventions included a workplace component (n = 4). Two interventions were reported as effective, and one partially effective. Conclusion The IM protocol is used in WDP since 2007. The participative dimension appears underused. Few theoretical frameworks were used. Implications are to better consider the stakeholders involvement, and mobilize theoretical frameworks with greater attempts to intervene on the work environment.

[Stereotactic hypofractionated radiation therapy as a bridge to transplantation for hepatocellular carcinoma: Case report of a complete pathological response and review of the literature]. / Place de la radiothérapie en conditions stéréotaxiques en traitement d'attente du carcinome hépatocellulaire avant transplantation hépatique : à propos d'un cas de réponse histologique complète sur explant et revue de la littérature.

Patients with hepatocellular carcinoma who are on liver transplant waiting list usually require local treatment to limit any risk of tumour growth. Historically percutaneous radiofrequency ablation or transarterial chemoembolization represented the major therapeutic alternatives. Depending on the size, or the topography of the lesion these two techniques may not be feasible. Radiation therapy under stereotactic conditions has recently emerged in the management of localized hepatocellular carcinoma as an alternative to the focused therapies performed to date. We herein report the case of a 43-year-old patient harbouring a complete histological response on explant after liver stereotactic irradiation and discuss its role in the management of hepatocellular carcinoma before liver transplantation.

The polyol process: a unique method for easy access to metal nanoparticles with tailored sizes, shapes and compositions.

After about three decades of development, the polyol process is now widely recognized and practised as a unique soft chemical method for the preparation of a large variety of nanoparticles which can be used in important technological fields. It offers many advantages: low cost, ease of use and, very importantly, already proven scalability for industrial applications. Among the different classes of inorganic nanoparticles which can be prepared in liquid polyols, metals were the first reported. This review aims to give a comprehensive account of the strategies used to prepare monometallic nanoparticles and multimetallic materials with tailored size and shape. As regards monometallic materials, while the preparation of noble as well as ferromagnetic metals is now clearly established, the scope of the polyol process has been extended to the preparation of more electropositive metals, such as post-transition metals and semi-metals. The potential of this method is also clearly displayed for the preparation of alloys, intermetallics and core-shell nanostructures with a very large diversity of compositions and architectures.

Changes in the use of end points in clinical trials for elderly cancer patients over time.

BACKGROUND: Physicians need well-addressed clinical trials assessing benefits and harm of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to present an overview of end points used in clinical trials dedicated to elderly patients; and to assess the evolution in chosen end points before and after the creation of the International Society of Geriatric Oncology in the early 2000s. PATIENTS AND METHODS: All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to identify subgroup analyses of elderly patients among these trials. RESULTS: Among phase III trials dedicated to elderly patients, overall survival was a common primary end point. Interestingly, tumor centered end points were very common in the first time period and very uncommon in the second time period, whereas composite end points were very uncommon in the first time period but very common in the second time period. Concerningly, disease-specific survival was very infrequently reported in dedicated clinical trials of elderly patients despite their importance in evaluating competing risk of death from non-oncology causes. The use of patient-reported outcomes (PROs) as a primary end point remained very uncommon but the reporting of PROs as a secondary end point tended to increase in the second time period, from 19% to 33% (P = 0.10). Functional status was infrequently reported. CONCLUSION: During the past decade, the use of clinically meaningful end points such as PROs and functional status in elderly patients remained moderate. Yet, the use of PROs as a secondary end point tended to increase between the two time periods.

Inclusion of elderly patients in oncology clinical trials.

BACKGROUND: Physicians need clinical trials assessing benefits and harms of treatments to avoid under-treatment or over-treatment of elderly patients. The main objectives of this report were to examine how data regarding elderly oncology patients were presented in medical literature; and to assess the evolution of this presentation between two time periods. PATIENTS AND METHODS: All phases I, II and III trials dedicated to the treatment of cancer among elderly patients published between 2001 and 2004 and between 2011 and 2014 were reviewed. All phase III clinical trials assessing cancer treatments among adults in the same periods were also reviewed to evaluate potential subgroup analyses in elderly patients in these studies. Key characteristics of interest were extracted by two investigators before descriptive and comparative analyses were undertaken. RESULTS: A total of 1084 trials were included: 366 and 718 from the first and second time period, respectively. Twenty-seven and 193 of these trials were phase I and II trials dedicated to elderly or frail patients, respectively. A large proportion of phase III trials published between 2011 and 2014 reported at least one analysis dedicated to elderly patients (46.7%) versus 19.3% during the first time period. The use of subgroup analyses of elderly patients in phase III trials was the most frequent source of information. Subgroup analyses were more frequent among trials with industrial funding, trials published in high impact factor journal, intercontinental trials and trials with large sample size. The age threshold defining the elderly subgroup increased over time. CONCLUSION: Elderly patients have become a topic of interest during the past decade. However, data available are mostly extracted from subgroup analyses, which can only be regarded as preliminary evidence.

[The intervention mapping protocol: A structured process to develop, implement and evaluate health promotion programs]. / Le protocole de l'intervention mapping : un processus méthodique pour élaborer, implanter et évaluer des programmes en promotion de la santé.

BACKGROUND: Health promotion programs are expected to improve population health and reduce social inequalities in health. However, their theoretical foundations are frequently ill-defined, and their implementation faces many obstacles. The aim of this article is to describe the intervention mapping protocol in health promotion programs planning, used recently in several countries. METHODS: The challenges of planning health promotion programs are presented, and the six steps of the intervention mapping protocol are described with an example. Based on a literature review, the use of this protocol, its requirements and potential limitations are discussed. RESULTS: The intervention mapping protocol has four essential characteristics: an ecological perspective (person-environment), a participative approach, the use of theoretical models in human and social sciences and the use of scientific evidence. It comprises six steps: conduct a health needs assessment, define change objectives, select theory-based change techniques and practical applications, organize techniques and applications into an intervention program (logic model), plan for program adoption, implementation, and sustainability, and generate an evaluation plan. This protocol was used in different countries and domains such as obesity, tobacco, physical activity, cancer and occupational health. Although its utilization requires resources and a critical stance, this protocol was used to develop interventions which efficacy was demonstrated. CONCLUSION: The intervention mapping protocol is an integrated process that fits the scientific and practical challenges of health promotion. It could be tested in France as it was used in other countries, in particular to reduce social inequalities in health.

HPLC & NMR-based forced degradation studies of ifosfamide: The potential of NMR in stability studies.

PURPOSE: The aim of this study is to conduct a forced degradation study on ifosfamide under several stress conditions to investigate the robustness of the developed HPLC method. It also aims to provide further insight into the stability of ifosfamide and its degradation profile using both HPLC and NMR. METHODS: Ifosfamide solutions (20mg/mL; n=15, 20mL) were stressed in triplicate by heating (70°C), under acidic (pH 1 & 4) and alkaline (pH 10 & 12) conditions. Samples were analysed periodically using HPLC and FT-NMR. RESULTS AND DISCUSSION: Ifosfamide was most stable under weakly acidic conditions (pH 4). NMR results suggested that the mechanism of ifosfamide degradation involves the cleavage of the PN bond. For all stress conditions, HPLC was not able to detect ifosfamide degradation products that were detected by NMR. CONCLUSION: These results suggest that the developed HPLC method for ifosfamide did not detect the degradation products shown by NMR. It is possible that degradation products co-elute with ifosfamide, do not elute altogether or are not amenable to the detection method employed. Therefore, investigation of ifosfamide stability requires additional techniques that do not suffer from the aforementioned shortcomings.

The reporting of adverse events in oncology phase III trials: a comparison of the current status versus the expectations of the EORTC members.

BACKGROUND: Determination of drug safety and tolerability is usually based on the frequency of certain key adverse events (AEs) rather than the frequency of all-grade toxicities. We assessed the reporting of key AEs in oncology randomized, controlled trials (RCTs) and compared that with the expectations of the European Organization for Research and Treatment of Cancer (EORTC) membership. MATERIALS AND METHODS: RCTs reports published between 2007 and 2011 were reviewed regarding the reporting of key AEs, namely: grade 3/4 AEs, grade 5 AEs, and AEs resulting in study withdrawal or in dose reduction. Study characteristics associated with better reporting of key AEs were investigated. Finally, a survey was conducted among the EORTC membership to determine their expectations on key AEs reporting. RESULTS: Although the frequency of grade 3/4 was reported in most reports (96%), only 17% of them described the reporting threshold above which grade 3/4 AEs were included for reporting, raising the possibility that important but less frequent grade 3/4 AEs might be underreported. Frequency and nature of grade 5 AEs were adequately reported in 161 (50%) of manuscripts; AEs leading to study withdrawal in 61 manuscripts (19%); and AEs leading to dose reduction in 43 manuscripts (13%). In contrast, most EORTC members expected a comprehensive reporting of grade 5 AEs (96% of EORTC member's responses), AEs leading to study withdrawal (86%) and AEs leading to dose reduction (70%). In multivariate analysis, frequencies of grade 5 AEs were less frequently reported in European trials (P = 0.004). Frequencies of AEs leading to withdrawals were more frequently reported in trials funded by industry (P = 0.005) and in trials including patients with breast or urological cancers (P = 0.006). CONCLUSIONS: These findings suggest that current practice of key AEs reporting remains highly variable and sometimes inadequate in oncology RCTs reports. Current standards for safety reporting in RCTs should be revised to emphasize the importance of key AEs reporting.

Neurologic Disorders in Immunocompetent Patients with Autochthonous Acute Hepatitis E.

Neurologic disorders, mainly Guillain-Barré syndrome and Parsonage­Turner syndrome (PTS), have been described in patients with hepatitis E virus (HEV) infection in industrialized and developing countries. We report a wider range of neurologic disorders in nonimmunocompromised patients with acute HEV infection. Data from 15 French immunocompetent patients with acute HEV infection and neurologic disorders were retrospectively recorded from January 2006 through June 2013. The disorders could be divided into 4 main entities: mononeuritis multiplex, PTS, meningoradiculitis, and acute demyelinating neuropathy. HEV infection was treated with ribavirin in 3 patients (for PTS or mononeuritis multiplex). One patient was treated with corticosteroids (for mononeuropathy multiplex), and 5 others received intravenous immunoglobulin (for PTS, meningoradiculitis, Guillain-Barré syndrome, or Miller Fisher syndrome). We conclude that pleiotropic neurologic disorders are seen in HEV-infected immunocompetent patients. Patients with acute neurologic manifestations and aminotransferase abnormalities should be screened for HEV infection.