Epidemiology of alcohol use disorder in the general population of Togo and Benin: the ALCOTRANS study.

INTRODUCTION: Access to data concerning mental health, particularly alcohol use disorders (AUD), in sub-Saharan Africa is very limited. This study aimed to estimate AUD prevalence and identify the associated factors in Togo and Benin. METHODS: A cross-sectional study was conducted between April and May 2022, targeting individuals aged 18 years and above in the Yoto commune of Togo and the Lalo commune of Benin. Subjects were recruited using a multi-stage random sampling technique. AUD diagnoses were made using the MINI adapted to DSM-5 criteria. Our study collected sociodemographic information, data on psychiatric comorbidities, stigmatization, and assessed cravings, using a series of scales. The association between AUD and various factors was analyzed using multivariable logistic regression. RESULTS: In Togo, 55 of the 445 people investigated had AUD (12.4%; [95% CI: 9.5-15.7%]). Among them, 39 (70.9%) had severe AUD and the main associated comorbidities were suicidal risk (36.4%), and major depressive disorder (16.4%). Associated factors with AUD were male gender (aOR: 11.3; [95% CI: 4.8-26.7]), a higher Hamilton Depression Rating Scale (HDRS) score (aOR: 1.2; [95% CI: 1.1-1.3]) and a lower Stigma score measured by the Explanatory Model Interview Catalogue (EMIC) (aOR: 0.9; [95% CI: 0.8-0.9). The stigma scores reflect perceived societal stigma towards individuals with AUD. In Benin, 38 of the 435 people investigated had AUD (8.7%; [95% CI: 6.4-11.7]), and the main associated comorbidities were suicidal risk (18.4%), tobacco use disorder (13.2%) and major depressive episode (16.4%). Associated factors with AUD were male gender (aOR: 6.4; [95% CI: 2.4-17.0]), major depressive disorder (aOR: 21.0; [95% CI: 1.5-289.8]), suicidal risk (aOR: 3.7; [95% CI: 1.2-11.3]), a lower Frontal Assessment Battery (FAB) score (aOR:0.8; [95% CI: 0.8-0.9]) and a lower perceived stigma score (by EMIC )(aOR: 0.9; [95% CI: 0.8-0.9]). CONCLUSION: In these communes of Togo and Benin, AUD prevalence is notably high. A deeper understanding of the disease and its local determinants, paired with effective prevention campaigns, could mitigate its impact on both countries.

The relationship between semantic and episodic memory: evidence from a case of severe anterograde amnesia.

It is increasingly being recognized that new declarative, consciously accessible information can be learned in anterograde amnesia, but it is not clear whether this learning is supported by episodic or semantic memory. We report a case of a 55-year-old man who experienced severe amnesia after limited damage to the medial temporal lobe following neurosurgical complications. His general cognitive performance and knowledge of new French words and public events that occurred before and after the onset of amnesia were assessed. Performance remained satisfactory on post-morbid vocabulary and public events, with a drop in performance observed for very recent public events only, while knowledge of very recent vocabulary was comparable to that of the control subjects. The implications of these findings for our understanding of the underlying learning mechanisms are discussed. This is the first report of acquisition of consciously accessible postmorbid knowledge of public events in a patient with severe amnesia.

Staging's determinants in early intervention youth: a retrospective study.

OBJECTIVES: Since 2019 our early intervention unit has assessed help-seekers, mainly referred by psychiatric departments, and we have conducted a descriptive retrospective study. Our objective was to identify clinical determinants associated to staging at assessment for our three groups: "no psychosis", "ultra-high risk" and "first episode psychosis". METHODS: One hundred and thirteen participants (mean age 20.05±3.28) were enrolled, mainly referred by adult psychiatry (81.4%). We tested the association of each group with the following determinants: age, gender, family history of psychosis, referral (adolescent or adult psychiatry), cognitive, depressive complaint, cannabis active consumption, and current activity (scholar or employment). RESULTS: Multivariate analyses showed significant association with depressive symptoms (P=0.019) but an absence of family history of psychosis (P=0.002) or current activity (P=0.09) for "no psychosis" group. "Ultra-high risk" was significantly correlated with a family history of psychosis (P=0.001) and adolescent psychiatry referral (P=0.044) but an absence of depressive complaint (P=0.04). As for "first episode psychosis", we found significant cognitive complaint (P=0.026), family history (P=0.024) and current activity (0.026). CONCLUSIONS: As all our participants were seen in tertiary care, adolescent psychiatrists were more efficient in detecting a high-risk state. "No psychosis" help-seekers presented in fact mood issues, which have been confused with attenuated psychotic symptoms by their addressers, who have probably been misled by their absence of activity integration. High-risk and characterized psychotic episodes were logically correlated with family history. Surprisingly, "first episode psychosis" youth were currently integrated in scholarly or professional life despite an active cognitive complaint. Robust studies, especially prospective cohorts, are needed to test these associations.

Innovative developments and emerging technologies in RNA therapeutics.

RNA-based therapeutics are emerging as a powerful platform for the treatment of multiple diseases. Currently, the two main categories of nucleic acid therapeutics, antisense oligonucleotides and small interfering RNAs (siRNAs), achieve their therapeutic effect through either gene silencing, splicing modulation or microRNA binding, giving rise to versatile options to target pathogenic gene expression patterns. Moreover, ongoing research seeks to expand the scope of RNA-based drugs to include more complex nucleic acid templates, such as messenger RNA, as exemplified by the first approved mRNA-based vaccine in 2020. The increasing number of approved sequences and ongoing clinical trials has attracted considerable interest in the chemical development of oligonucleotides and nucleic acids as drugs, especially since the FDA approval of the first siRNA drug in 2018. As a result, a variety of innovative approaches is emerging, highlighting the potential of RNA as one of the most prominent therapeutic tools in the drug design and development pipeline. This review seeks to provide a comprehensive summary of current efforts in academia and industry aimed at fully realizing the potential of RNA-based therapeutics. Towards this, we introduce established and emerging RNA-based technologies, with a focus on their potential as biosensors and therapeutics. We then describe their mechanisms of action and their application in different disease contexts, along with the strengths and limitations of each strategy. Since the nucleic acid toolbox is rapidly expanding, we also introduce RNA minimal architectures, RNA/protein cleavers and viral RNA as promising modalities for new therapeutics and discuss future directions for the field.

Effectiveness of Repetitive Transcranial Magnetic Stimulation on Fibromyalgia Patients Responding to a First Repetitive Transcranial Magnetic Stimulation Induction Course After Six Months of Maintenance Treatment: A Randomized Pilot-Controlled Study.

BACKGROUND: Fibromyalgia is a chronic painful condition without real, effective treatment. The administration of repetitive transcranial magnetic stimulation (rTMS) has been shown to have a therapeutic effect on pain, but there are still questions about the maintenance of its effect over time. Continuation of the treatment upon clinical response through maintenance sessions is promising and merits further exploration. MATERIALS AND METHODS: We conducted a randomized, parallel-group, controlled study involving 78 patients to evaluate the effect of rTMS vs sham stimulation after a three-week induction treatment and six months of maintenance treatment (three-week periodicity) on 22 patients who presented a clinical response to the induction treatment. The clinical response was defined as a ≥30% decrease of the baseline visual analog scale (VAS) for pain and a score for the Patient Global Impression of Change (PGIC) >5. The clinic global impression, fibromyalgia impact questionnaire, symptom severity score, and Beck's depression inventory were also studied. RESULTS: A significant clinical response to treatment with rTMS was observed after the induction phase and maintained over six months, particularly as measured by the PGIC parameter of pain, as well as of the intensity of fatigue and depression, with an absence of adverse effects induced by this method. CONCLUSION: A three-week rTMS treatment, characterized by a reduction in pain, as evaluated by VAS, should be continued with the administration of rTMS maintenance sessions for an additional six months to maintain the best possible long-term effects.

Sensory processing in depression: Assessment and intervention perspective.

Few studies have examined sensory processing in mood disorders, including depression. The interactions between sensory inputs and adaptive behaviour have yet to be clarified in this pathology. We assessed sensory profiles among people with major depressive disorder (MDD) with the Adult/Adolescent Sensory Profile scale and determined whether sensory processing patterns were associated with clinical variables such as anxiety, depression, psychomotor retardation or self-esteem. We compared 25 participants with MDD (MDD group) and 25 healthy controls (HC group) to identify sensory processing patterns (low registration, sensation seeking, sensory sensitivity and sensation avoiding). The Hamilton Depression Rating Scale and Clinical Outcomes in Routine Evaluation scale were used to assess depressive symptomatology. Both groups completed the Hamilton Anxiety Rating Scale, Frontal Assessment Battery and Rosenberg Self-Esteem Inventory. The MDD group significantly differed from the HC group in each sensory processing patterns. They had higher low registration (p < 0.001), sensory sensitivity (p < 0.001) and sensation avoidance (p < 0.001) and lower sensation seeking (p = 0.005) than HC. Extreme sensory processing patterns in MDD patients were linked to depressive symptomatology, including anxiety. Sensory processing disorders should be assessed and taken into account when developing nondrug treatment strategies.

A New Label-Free Approach to Glioblastoma Cancer Stem Cell Sorting and Detection.

Cancer stem cells (CSCs) play critical roles in cancer, making them important targets for new diagnostic and therapeutic approaches. Since CSCs are heterogeneous and not abundant in tumors, and few specific markers for these cells currently exist, new methods to isolate and characterize them are required. To address this issue, we developed a new label-free methodology to isolate, enrich, and identify CSCs from an heterogeneous tumor cell subpopulation using a cell sorting method (sedimentation field flow fractionation, SdFFF) and a biosensor as a detector. Enrichment was optimized using an original protocol and U87-MG glioblastoma cells cultured in a normal (N) or defined (D) medium (± fetal bovine serum, FBS) under normoxic (N, pO2 = 20%) or hypoxic (H, pO2 < 2%) conditions to obtain four cell populations: NN, NH, DN, and DH. After elution of CSCs via SdFFF using the hyperlayer mode (inertial elution mode for micrometer-sized species), we isolated eight subpopulations with distinct CSC contents based on phenotypical and functional properties, ranging from NN F1 with a lower CSC content to DH F3 with a higher CSC content. Reflecting biological differences, the intrinsic intracellular dielectric permittivity increased from NN to DH conditions. The largest difference in electromagnetic signature was observed between NN F1 and DH F3, in which the CSC content was lowest and highest, respectively. The results demonstrate that microwave dielectric spectroscopy can be used to reliably and efficiently distinguish stem cell characteristics. This new instrumental and methodological approach is an important innovation that allows both enrichment and detection of CSCs, opening the door to novel diagnostic and therapeutic approaches.

Autophagy and TrkC/NT-3 signaling joined forces boost the hypoxic glioblastoma cell survival.

Glioblastoma multiform (GBM), the most common and aggressive primary brain tumor, is characterized by a high degree of hypoxia and resistance to therapy because of its adaptation capacities, including autophagy and growth factors signaling. In this study, we show an efficient hypoxia-induced survival autophagy in four different GBM cell lines (U87MG, M059K, M059J and LN-18) and an activation of a particular neurotrophin signaling pathway. Indeed, the enhancement of both TrkC and NT-3 was followed by downstream p38MAPK phosphorylation, suggesting the occurrence of a survival autocrine loop. Autophagy inhibition increased the hypoxia-induced expression of TrkC and its phosphorylated form as well as the phosphorylation of p38, suggesting a complementary effect of the two processes, leading to cell survival. Alone, autophagy inhibition reduced cellular growth without inducing cell death. However, the double inhibition of autophagy and TrkC signaling was necessary to bring cells to death as shown by PARP cleavage, particularly important in hypoxia. Moreover, a very high expression of TrkC and NT-3 was found in tumor sections from GBM patients, highlighting the importance of neurotrophic signaling in GBM tumor cell survival. These data suggest that a combined treatment targeting these two pathways could be considered in order to induce the death of GBM cells.

KLRC3, a Natural Killer receptor gene, is a key factor involved in glioblastoma tumourigenesis and aggressiveness.

Glioblastoma is the most lethal brain tumour with a poor prognosis. Cancer stem cells (CSC) were proposed to be the most aggressive cells allowing brain tumour recurrence and aggressiveness. Current challenge is to determine CSC signature to characterize these cells and to develop new therapeutics. In a previous work, we achieved a screening of glycosylation-related genes to characterize specific genes involved in CSC maintenance. Three genes named CHI3L1, KLRC3 and PRUNE2 were found overexpressed in glioblastoma undifferentiated cells (related to CSC) compared to the differentiated ones. The comparison of their roles suggest that KLRC3 gene coding for NKG2E, a protein initially identified in NK cells, is more important than both two other genes in glioblastomas aggressiveness. Indeed, KLRC3 silencing decreased self-renewal capacity, invasion, proliferation, radioresistance and tumourigenicity of U87-MG glioblastoma cell line. For the first time we report that KLRC3 gene expression is linked to glioblastoma aggressiveness and could be a new potential therapeutic target to attenuate glioblastoma.

Development of DNA Nanostructures for High-Affinity Binding to Human Serum Albumin.

The development of nucleic acid therapeutics has been hampered by issues associated with their stability and in vivo delivery. To address these challenges, we describe a new strategy to engineer DNA structures with strong binding affinity to human serum albumin (HSA). HSA is the most abundant protein in the blood and has a long circulation half-life (19 days). It has been shown to hinder phagocytosis, is retained in tumors, and aids in cellular penetration. Indeed, HSA has already been successfully used for the delivery of small-molecule drugs and nanoparticles. We show that conjugating dendritic alkyl chains to DNA creates amphiphiles that exhibit high-affinity (Kd in low nanomolar range) binding to HSA. Notably, complexation with HSA did not hinder the activity of silencing oligonucleotides inside cells, and the degradation of DNA strands in serum was significantly slowed. We also show that, in a site-specific manner, altering the number and orientation of the amphiphilic ligand on a self-assembled DNA nanocube can modulate the affinity of the DNA cage to HSA. Moreover, the serum half-life of the amphiphile bound to the cage and the protein was shown to reach up to 22 hours, whereas unconjugated single-stranded DNA was degraded within minutes. Therefore, adding protein-specific binding domains to DNA nanostructures can be used to rationally control the interface between synthetic nanostructures and biological systems. A major challenge with nanoparticles delivery is the quick formation of a protein corona (i.e., protein adsorbed on the nanoparticle surface) upon injection to biological media. We foresee such DNA cage-protein complexes as new tools to study the role of this protein adsorption layer with important implications in the efficient delivery of RNAi therapeutics in vitro and in vivo.

Effectiveness of the Therapeutic Community Model in Addiction Treatment: A Retrospective Pilot Study in French Prisons.

BACKGROUND: In France, addiction care in prison usually consists of nurses' interventions, medical care and socio-educational programs, but new alternatives have arisen, namely the therapeutic community (TC) model. This pilot study aims to evaluate the effectiveness of this prison-based TC in comparison with classic and socio-educational care offered in French prisons. METHODS: To compare these three types of prison-based care, two detention centers' files were screened for use of multiple drugs, willingness to participate and absence of psychiatric comorbidities incompatible with group therapy. A custom questionnaire was built based on the fifth version of the Addiction Severity Index. It investigates medical status, employment and support, primary addiction status, legal status, social/familial status and psychiatric status through various items. RESULTS: Our sample only consisted of male repeat offenders with a mean age of 37.7 ± (9.1) years. Primary addiction status improvement was observed for all care studied but was more important in TC than in classic care. Self-esteem and social/familial status saw significant improvement throughout TC care. CONCLUSIONS: The TC model represents an alternative to classic and socio-educational care in French prisons. More studies are needed to assess the extent of the benefits provided on both the medical side and economic side.

Predictive factors for acceptance of a long-acting opiate substitution treatment studied through social representations and internalized stigma.

OBJECTIVES: Opioid use disorder is a public health problem worldwide with a treatment gap partially due to sociocultural representation and stigma. Taking the opportunity of an authorization to a subcutaneous (SC) injectable solution of buprenorphine, the first and only injectable treatment for opioid dependence available in France, we investigate potential obstacles to its implementation in France. METHODS: This study aimed to define the factors predicting the acceptance of a new SC form of opiate substitution treatment (OST) by comparing the social representations using an adapted version of the Explanatory Model Interview Catalogue (EMIC) and the internalized stigma of intravenous drug injection using the Internalized Stigma of Mental Illness Inventory (ISMI) between participants receiving OST likely to accept the SC form or not. We also observed whether the fear of an opiate withdrawal syndrome could influence this choice. RESULTS: Fifty OST patients were included, 54% of them accepted a new SC form of OST. Perceived causes of drug injection measured with EMIC were significantly lower among participants who would not accept the new SC form. No significant difference was found regarding the total score of the adapted ISMI or its items. The fear of opiate withdrawal syndrome did not seem to be statistically related to acceptance of a long-acting SC OST in either group. The most discriminating combination of factors in predicting patient acceptance of such treatment was related to the perceived causes of drug injection associated with a severe Diagnostic and Statistical Manual of Mental Disorders 5th version (DSM-5) diagnosis, and a lower alcohol consumption. CONCLUSIONS: We observed significant differences in social representations but not in internalized stigma between the two groups. Moreover, the predictive factors linked to the acceptance of a new SC form of OST suggest a multifactorial combination of elements that will have to be tested in a larger and prospective study delivering long-acting high-dose buprenorphine.

BDNF CpG methylation and serum levels covary during alcohol withdrawal in patients with alcohol use disorder: A pilot study.

OBJECTIVES: Brain-derived neurotrophic factor (BDNF) levels vary in various conditions including alcohol use disorder (AUD). We aimed to identify drivers of these variations. METHODS: Twelve patients with AUD were assessed at hospitalisation for alcohol withdrawal and four months later. We looked for associations between the change in serum BDNF levels and (1) length of abstinence, (2) anxiety (Hamilton Anxiety Scale) and depression (Beck-Depression Inventory), (3) one functional BDNF genotype (rs6265) and (4) methylation levels of 12 CpG sites within the BDNF gene (located in exons I, IV and IX). RESULTS: While abstinence remained, serum BDNF level increased. This increase correlated with the variation of methylation levels of the BDNF gene, and more specifically of exon I. We found no significant effect of length of abstinence, rs6265, depression or anxiety on serum BDNF level. CONCLUSIONS: Epigenetic regulation of the BDNF gene may be involved in variations of BDNF blood level associated with alcohol abstinence.

Distinct Predictors of Clinical Response after Repetitive Transcranial Magnetic Stimulation between Bipolar and Unipolar Disorders.

Background: Repetitive transcranial magnetic stimulation (rTMS) has been shown to be therapeutically effective for patients suffering from drug-resistant depression. The distinction between bipolar and unipolar disorders would be of great interests to better adapt their respective treatments. Methods: We aimed to identify the factors predicting clinical improvement at one month (M1) after the start of rTMS treatment for each diagnosis, which was preceded by a comparison of the patients' clinical conditions. We used the data collected and the method employed in a previous publication on 291 patients. Results: Although the bipolar group had fewer responders, these patients seemed to better maintain their post-rTMS improvement on anxiety and perception of the severity of their illness than those in the unipolar group. For the bipolar group, young age coupled with low number of medications and high fatigue was shown to be the best combination for predicting improvement at M1. The duration of current depressive episode, which was previously demonstrated for whole group, combined with being attached was shown to favor clinical improvement among the patients in unipolar group. Conclusion: We were able to define a combination of specific factors related to each diagnosis for predicting the patients' clinical response. This could be extremely useful to predict the efficacy of rTMS during routine clinical practice in neuromodulation services.

Comparison of withdrawal symptom intensity between hypnosis and nicotine-replacement-therapies: A pilot study.

Smoking cessation is a global public health issue. Nicotine dependence is a dynamic process that is not limited to physical dependence. Hypnosis can be helpful in the global management of smoking cessation. We explored this effect by comparing the effects of hypnosis and nicotine-replacement therapies (NRT) on tobacco withdrawal.Thirty participants were included in this comparative-randomized pilot study in parallel controlled groups after ethical validation. Participants were recruited by a general practitioner and had standardized consultations with addiction and hypnosis specialists and adapted treatment. The evolution of withdrawal symptoms was compared using the Cigarette Withdrawal Scale-21 for one month after smoking cessation in an adult tobacco-addict population wishing to stop smoking and receiving either NRT or hypnosis, both supported by motivational interviews. Craving intensity (French version of the Tobacco Craving Questionnaire), nicotine dependence (Fagerström), tobacco consumption, anxiety (Hamilton scale), and depression (Montgomery-Asberg scale) were also evaluated. Hypnosis appeared to have an influence on reducing the number of smoked cigarettes, whereas NRT appeared to influence markers of both physical and psychic dependence. A complementarity of hypnosis and NRT may be a viable therapeutic alternative to reduce the intensity of withdrawal symptoms after voluntary smoking cessation. A study on a larger population with a longer follow-up is needed to assess the advantages of each method to quit smoking.

Detection of Glycosylated Markers From Cancer Stem Cells With ColoSTEM Dx Kit for Earlier Prediction of Colon Cancer Aggressiveness.

Nowadays, colon cancer prognosis still difficult to predict, especially in the early stages. Recurrences remain elevated, even in the early stages after curative surgery. Carcidiag Biotechnologies has developed an immunohistochemistry (IHC) kit called ColoSTEM Dx, based on a MIX of biotinylated plant lectins that specifically detects colon cancer stem cells (CSCs) through glycan patterns that they specifically (over)express. A retrospective clinical study was carried out on tumor tissues from 208 non-chemotherapeutic-treated and 21 chemotherapeutic-treated patients with colon cancer, which were stained by IHC with the MIX. Clinical performances of the kit were determined, and prognostic and predictive values were evaluated. With 78.3% and 70.6% of diagnostic sensitivity and specificity respectively, our kit shows great clinical performances. Moreover, patient prognosis is significantly poorer when the MIX staining is "High" compared to "Low", especially at 5-years of overall survival and for early stages. The ColoSTEM Dx kit allows an earlier and a more precise determination of patients' outcome. Thus, it affords an innovating clinical tool for predicting tumor aggressiveness earlier and determining prognosis value regarding therapeutic response in colon cancer patients.

DNA Nanostructures: Current Challenges and Opportunities for Cellular Delivery.

DNA nanotechnology has produced a wide range of self-assembled structures, offering unmatched possibilities in terms of structural design. Because of their programmable assembly and precise control of size, shape, and function, DNA particles can be used for numerous biological applications, including imaging, sensing, and drug delivery. While the biocompatibility, programmability, and ease of synthesis of nucleic acids have rapidly made them attractive building blocks, many challenges remain to be addressed before using them in biological conditions. Enzymatic hydrolysis, low cellular uptake, immune cell recognition and degradation, and unclear biodistribution profiles are yet to be solved. Rigorous methodologies are needed to study, understand, and control the fate of self-assembled DNA structures in physiological conditions. In this review, we describe the current challenges faced by the field as well as recent successes, highlighting the potential to solve biology problems or develop smart drug delivery tools. We then propose an outlook to drive the translation of DNA constructs toward preclinical design. We particularly believe that a detailed understanding of the fate of DNA nanostructures within living organisms, achieved through thorough characterization, is the next required step to reach clinical maturity.

Acceptability of Pharmacogenetic Testing among French Psychiatrists, a National Survey.

Psychiatric disorder management is based on the prescription of psychotropic drugs. Response to them remains often insufficient and varies from one patient to another. Pharmacogenetics explain part of this variability. Pharmacogenetic testing is likely to optimize the choice of treatment and thus improve patients' care, even if concerns and limitations persist. This practice of personalized medicine is not very widespread in France. We conducted a national survey to evaluate the acceptability of this tool by psychiatrists and psychiatry residents in France, and to identify factors associated with acceptability and previous use. The analysis included 397 observations. The mean acceptability score was 10.70, on a scale from 4 to 16. Overall acceptability score was considered as low for 3.0% of responders, intermediate for 80.1% and high for 16.9%. After regression, the remaining factors influencing acceptability independently of the others were prescription and training history and theoretical approach. The attitude of our population seems to be rather favorable, however, obvious deficiencies have emerged regarding perceived skills and received training. Concerns about the cost and delays of tests results also emerged. According to our survey, one of the keys to overcoming the barriers encountered in the integration of pharmacogenetics seems to be the improvement of training and the provision of information to practitioners.

Predictors of clinical response after rTMS treatment of patients suffering from drug-resistant depression.

Repeated transcranial magnetic stimulation (rTMS) is a therapeutic brain-stimulation technique that is particularly used for drug-resistant depressive disorders. European recommendations mention the effectiveness of 30 to 64%. The failure rate of treatment is high and clinical improvement is visible only after a certain period of time. It would thus be useful to have indicators that could anticipate the success of treatment and more effectively guide therapeutic choices. We aimed to find predictive indicators of clinical improvement at 1 month after the start of rTMS treatment among the data collected during the care of patients with drug-resistant depression included in the Neuromodulation Unit of the Esquirol Hospital in Limoges since 2007. In total, 290 patients with a pharmaco-resistant depressive episode, according to the Hamilton Depression Rating Scale (HDRS) (score ≥8), before treatment who underwent a complete course of rTMS treatment and did not object to the use of their collected data were included. The clinical response in routine practice, corresponding to a decrease in the HDRS score of at least 50% from inclusion, was determined and complemented by interquartile analysis. A combination of factors predictive of clinical response during care, such as a short duration of the current depressive episode associated with a higher HDRS agitation item value (or a lower perceived sleepiness value) and a higher number of previous rTMS treatments, were identified as being useful in predicting the efficacy of rTMS treatment in routine clinical practice, thus facilitating the therapeutic choice for patients with drug-resistant depression.

Detailed cellular assessment of albumin-bound oligonucleotides: Increased stability and lower non-specific cell uptake.

Conjugation of lipid moieties to nucleic-acid therapeutics increases their interaction with cellular membranes, enhances their uptake and influences in vivo distribution. Once injected in biological fluids, such modifications trigger the binding of various serum proteins, which in turn play a major role in determining the fate of oligonucleotides. Yet, the role played by each of these proteins, more than 300 in serum, remains to be elucidated. Albumin, the most abundant circulating protein is an attractive candidate to study, as it was previously used to enhance the therapeutic effect of various drugs. Herein, we present a thorough fluorescent-based methodology to study the effect of strong and specific albumin-binding on the fate and cellular uptake of DNA oligonucleotides. We synthesized a library of molecules that exhibit non-covalent binding to albumin, with affinities ranging from high (nanomolar) to none. Our results revealed that strong albumin binding can be used as a strategy to reduce degradation of oligonucleotides in physiological conditions caused by enzymes (nucleases), to reduce uptake and degradation by immune cells (macrophages) and to prevent non-specific uptake by cells. We believe that introducing protein-binding domains in oligonucleotides can be used as a strategy to control the fate of oligonucleotides in physiological environments. While our study focuses on albumin, we believe that such systematic studies, which elucidate the role of serum proteins systematically, will ultimately provide a toolbox to engineer the next-generation of therapeutic oligonucleotides, overcoming many of the barriers encountered by these therapeutics, such as stability, immunogenicity and off-target effects.