Are SCN2A-related BFNISs also responsible for seizures in adulthood? A case report opens new scenarios.

Large cohort studies and variant-specific electrophysiology have enabled the delineation of different SCN2A-epilepsy phenotypes, phenotype-genotype correlations, prediction of pharmacosensitivity to sodium channel blockers, and long-term prognostication for clinicians and families. One of the most common clinical presentations of SCN2A pathological variants is benign familial neonatal-infantile seizures (BFNIS), which are characterized by seizure onset between the first day of life and 23 months of age and typically resolve, either spontaneously or with the aid of sodium channel blockers, within the first 2 years of life. In 2004, Berkovic et al. reported the case of a young boy affected by SCN2A-related BFNIS whose mother, who carried the same pathological variant, had also presented with BFNIS in infancy. Our case report focuses on the aforementioned woman who, more than 40 years later, presented two additional seizures, therefore opening the possibility of a role for SCN2A-related seizures in adulthood.

COVID-19 infection-associated platelet and neutrophil activation is blunted by previous anti-SARS-CoV-2 vaccination.

The effectiveness of vaccination against SARS-CoV-2 in preventing COVID-19 or in reducing severe illness in subjects hospitalized for COVID-19 despite vaccination has been unequivocally shown. However, no studies so far have assessed if subjects who get COVID-19 despite vaccination are protected from SARS-CoV-2-induced platelet, neutrophil and endothelial activation, biomarkers associated with thrombosis and worse outcome. In this pilot study, we show that previous vaccination blunts COVID-19-associated platelet activation, assessed by circulating platelet-derived microvesicles and soluble P-selectin, and neutrophil activation, assessed by circulating neutrophil extracellular trap (NET) biomarkers and matrix metalloproteinase-9, and reduces COVID-19-associated thrombotic events, hospitalization in intensive-care units and death.

Improvement in binge eating and alexithymia predicts weight loss at 9-month follow-up of the lifestyle modification program.

PURPOSE: The aim of this longitudinal study was to examine the extent to which improved levels of binge eating (BE) behaviors, alexithymia, self-esteem, and psychological distress would predict a reduction in body mass at 9-month follow-up, following a lifestyle modification program for weight loss in obese or overweight patients. METHODS: A convenience sample of 120 obese or overweight patients were recruited. Body mass index (BMI), binge eating (BES), levels of alexithymia (TAS-20), perceived stress (PSS), depressive symptoms (SDS), and self-esteem (RSE) were assessed during their first medical examination (T1), and after a weight-loss treatment period of 9 months (T2). RESULTS: Compared with unimproved patients, improved patients reported a significant decrease in binge eating (p = 0.04) and perceived stress symptoms (p = 0.03), and a significant improvement in self-esteem (p = 0.02) over time. After controlling for gender, self-esteem, depressive symptoms, and perceived stress, baseline BMI (OR = 1.11, 95% CI [1.04,1.19]), ΔBES (OR = 0.99, 95% CI [0.98,0.99]), and ΔTAS-20 (OR = 1.03, 95% CI [1.01,1.05]) significantly and independently predicted a ≥ 5% reduction in body mass from baseline. CONCLUSIONS: Our finding supports the suggestion to consider psychological outcomes such as emotional aspects and dysfunctional eating behaviors when planning a weight loss programs to prevent a negative outcome. LEVEL OF EVIDENCE:  Level III, case-control analytic study.

More Than Meets the Eye: A Case of Breast Cancer Switching from Being Luminal-Androgen-Receptor-Positive to Being Hormone-Receptor-Positive.

Triple-negative breast cancer (TNBC) represents about 15% of all breast cancers and is usually characterized by aggressive clinical behavior and a poor prognosis. Four TNBC subgroups have been previously defined with different molecular profiles: (i) luminal androgen receptor (LAR), (ii) mesenchymal (MES), (iii) basal-like immunosuppressed (BLIS) and (iv) basal-like immune-activated (BLIA). Among these, LAR is characterized by the expression of the androgen receptor (AR), and exhibits genomic characteristics that resemble luminal breast cancers, with a still undefined prognosis and clinical behavior. Here, we report a case of a woman affected by recurring LAR TNBC, which underwent phenotypic changes throughout its natural history. After the initial diagnosis of LAR breast cancer, the patient experienced local recurrence with strong expression of the estrogen receptor. Due to this finding, she started treatment with a CDK4/6-inhibitor and an aromatase inhibitor, followed by oral vinorelbine, both with dismal outcomes. Then, she received everolimus and exemestane, which determined temporary disease stabilization. An extensive NGS analysis of tumor tissue showed PIK3CA and HER2 mutations. Our case is consistent with previous reports of LAR breast cancer and underlines the potential utility of re-biopsy and molecular testing in breast cancer (BC), especially in rare subtypes.

HDAC11 deficiency disrupts oncogene-induced hematopoiesis in myeloproliferative neoplasms.

Protein acetylation is an important contributor to cancer initiation. Histone deacetylase 6 (HDAC6) controls JAK2 translation and protein stability and has been implicated in JAK2-driven diseases best exemplified by myeloproliferative neoplasms (MPNs). By using novel classes of highly selective HDAC inhibitors and genetically deficient mouse models, we discovered that HDAC11 rather than HDAC6 is necessary for the proliferation and survival of oncogenic JAK2-driven MPN cells and patient samples. Notably, HDAC11 is variably expressed in primitive stem cells and is expressed largely upon lineage commitment. Although Hdac11is dispensable for normal homeostatic hematopoietic stem and progenitor cell differentiation based on chimeric bone marrow reconstitution, Hdac11 deficiency significantly reduced the abnormal megakaryocyte population, improved splenic architecture, reduced fibrosis, and increased survival in the MPLW515L-MPN mouse model during primary and secondary transplantation. Therefore, inhibitors of HDAC11 are an attractive therapy for treating patients with MPN. Although JAK2 inhibitor therapy provides substantial clinical benefit in MPN patients, the identification of alternative therapeutic targets is needed to reverse MPN pathogenesis and control malignant hematopoiesis. This study establishes HDAC11 as a unique type of target molecule that has therapeutic potential in MPN.

Alexithymia and metabolic syndrome: the mediating role of binge eating.

PURPOSE: Alexithymia, a personality trait characterized by difficulties in emotional processing, has been associated with unhealthy behaviors and chronic medical conditions. This study aimed to further develop our understanding of this complex relationship by investigating whether alexithymia increases the risk of metabolic syndrome (MetS) in participants with obesity or overweight through the mediating role of binge eating (BE). METHODS: A consecutive sample of 238 treatment-seeking patients with obesity or overweight were recruited. Alexithymia (TAS-20), binge eating symptoms (BES), body mass index (BMI), and depression and anxiety symptoms (HADS) were concurrently assessed. RESULTS: Almost half of the participants met the criteria for MetS (44.12%). Compared to patients without MetS, those with MetS were older, had a longer duration of overweight, and had a higher BMI (p < 0.01). Individual with MetS also had higher HADS, BES, and TAS-20 scores, particularly difficulty identifying and describing feelings. The structural equation modeling (SEM) analysis revealed that BES levels exerted a significant direct effect on MetS (p < 0.01), and that TAS-20 levels exerted a significant direct effect on BES (p < 0.01), anxiety (p < 0.001) and depression (p < 0.001). Moreover, psychological distress (anxiety, p = 0.01, and depression, p = .05) indirectly affected MetS through the mediating effect of BES, and TAS-20 (p = 0.01) indirectly affected MetS through the mediating effect of HADS and BES. Finally, age had a significant direct effect on MetS (p < 0.001). CONCLUSION: Our findings indicate that alexithymia is a concurrent causative factor to the development of MetS through the mediating role of BE and psychological distress. LEVEL OF EVIDENCE: Level III, case-control analytic study.

What is the "weight" of body mass index on sexual functioning in women? A mediation model.

PURPOSE: It is well known that body mass index (BMI) affects how individuals perceive their well-being and that obese individuals tend to report poorer levels of subjective health status. The aim of this study was to compare subjects with and without FSD and to examine the direct and indirect impact of BMI on female sexual dysfunction (FSD) in overweight/obese and normal-weight women. METHODS: A cross-sectional study was conducted on 186 overweight/obese and 233 normal-weight women. FSD assessed with the Female Sexual Function Index (FSFI) was investigated in relation to body satisfaction assessed with the Body Uneasiness Test (BUT-A) and self-esteem assessed with the Rosenberg Self-Esteem scale (RSE). RESULTS: No difference in the prevalence of FSD was found between overweight/obese (44.4%) and normal-weight women (55.6%), even though significant between-group differences in body image were found. Structural Equation Modelling (SEM) showed that BMI contribute to FSD only through the mediating role of body dissatisfaction and self-esteem. CONCLUSIONS: The present results support the notion that sexual functioning is not related directly to BMI in women but to a more complex interactions of body weight, satisfaction with one's own body image, and levels of self-esteem. Clinicians should take into account that for women having a good sexual life seems not related to body weight but to the way their body weight is perceived within the context of self-image. LEVEL OF EVIDENCE: Level III, case-control analytic study.

Alexithymia and binge eating in obese outpatients who are starting a weight-loss program: A structural equation analysis.

OBJECTIVE: To investigate whether obese patients with binge eating (BE) have higher alexithymic features; to explore the different relationships between psychological features (alexithymia, depression, and anxiety) and BE. METHOD: Three hundred sixty one obese BE-patients were evaluated for alexithymia, psychological distress, and BE. Alexithymia was measured with the 20-item Toronto Alexithymia Scale (TAS-20); BE was assessed with the BE Scale (BES), and depression and anxiety symptoms were evaluated with the Hospital Anxiety and Depression Scale (HADS). RESULTS: Patients with BE reported significantly higher TAS-20 total scores than those without BE (p < .001). The SEM analysis showed that the difficulty in identifying feelings (DIF) and difficulty in describing feelings (DDF) components of alexithymia affected BE along different pathways. DIF was found as a major factor influencing altered eating both directly (p = .20*) and above all through the mediation of psychological distress (p = .19***), whereas DDF affected BE only through psychological distress at a lesser extent (p = .09**). DISCUSSION: Alexithymic difficulties in affective awareness may play an important role in the onset and maintenance of BE, especially when patients experienced anxiety and depression symptoms. Clinicians involved in the management of obesity should address the combination of alexithymic traits and emotional distress by planning effective client-focused interventions.

Discovery of novel N-hydroxy-2-arylisoindoline-4-carboxamides as potent and selective inhibitors of HDAC11.

N-Hydroxy-2-arylisoindoline-4-carboxamides are potent and selective inhibitors of HDAC11. The discovery, synthesis, and structure activity relationships of this novel series of inhibitors are reported. An advanced analog (FT895) displays promising cellular activity and pharmacokinetic properties that make it a useful tool to study the biology of HDAC11 and its potential use as a therapeutic target for oncology and inflammation indications.

Floating modular drug delivery systems with buoyancy independent of release mechanisms to sustain amoxicillin and clarithromycin intra-gastric concentrations.

Release modules of amoxicillin and clarithromycin combined in a single dosage form designed to float in the gastric content and to sustain the intra-gastric concentrations of these two antibiotics used for the eradication of Helicobacter pylori have been studied. The modules having a disc shape with curved bases were formulated as hydrophilic matrices. Two modules of clarithromycin were assembled by sticking the concave base of one module to the concave base of the other, creating an internal void chamber. The final dosage form was a floating assembly of three modules of clarithromycin and two of amoxicillin in which the drug release mechanism did not interfere with the floatation mechanism. The assembled system showed immediate in vitro floatation at pH 1.2, lasting 5 h. The in vitro antibiotics release profiles from individual modules and assembled systems exhibited linear release rate during buoyancy for at least 8 h. The predicted antibiotic concentrations in the stomach maintained for long time levels significantly higher than the respective minimum inhibitory concentrations (MIC). In addition, an in vivo absorption study performed on beagle dogs confirmed the slow release of clarithromycin and amoxicillin from the assembled system during the assembly's permanence in the stomach for at least 4 h.

Antibody-Drug Conjugates to Promote Immune Surveillance: Lessons Learned from Breast Cancer.

Antibody-drug conjugates (ADCs) represent an effective class of agents for the treatment of several tumor types, including breast cancer (BC), featuring approved molecules such as trastuzumab-emtansine, trastuzumab-deruxtecan, and sacituzumab-govitecan. Immune-checkpoint inhibitors (ICIs) also showed activity in selected BC subtypes, and two agents, pembrolizumab and atezolizumab, are currently approved for the treatment of triple-negative BC patients. The potential synergy between ADCs and immunotherapy in BC remains an area of active investigation. Preclinical studies suggest that ADCs promote immune surveillance, modulating tumor microenvironment, inducing immunogenic cell death, and enhancing antitumor immunity. Translational evidence has shown potential predictive biomarkers for ADCs alone or in combination with immunotherapy, including expression of target antigen, oncogenic pathways, tumor-infiltrating lymphocytes, and neutrophil-to-lymphocyte ratio. Given this background, several clinical trials evaluated ADC-ICI combinations in BC patients, demonstrating promising outcomes with an overall manageable toxicity profile, and many studies are currently ongoing to confirm the efficacy and feasibility of this therapeutic approach. In the present review, we summarized the available evidence about the integration of ADCs and immunotherapy for the management of BC, emphasizing the need for further translational and clinical investigations to optimize this treatment strategy and elucidate predictive biomarkers, eventually improving patient outcomes.

Emotions in search of words: Does alexithymia predict treatment outcome in chronic musculoskeletal pain?

Chronic pain, with its complex and multidimensional nature, poses significant challenges in identifying effective long-term treatments. There is growing scientific interest in how psychopathological and personality dimensions may influence the maintenance and development of chronic pain. This longitudinal study aimed to investigate whether alexithymia can predict the improvement of pain severity following a treatment-as-usual programme for chronic musculoskeletal pain over and above psychological cofactors (emotional distress, catastrophizing, and self-efficacy). A consecutive sample of 129 patients with diagnosed chronic musculoskeletal pain referred to two tertiary care centres was recruited and treated for 16 weeks. Clinical pain, psychological distress, self-efficacy, catastrophizing, and alexithymia were assessed with validated self-report measures at the first medical visit (T0) and at 16-week follow-up (T1). Compared with non-responder patients (n = 72, 55.8%), those who responded (i.e., reduction of >30% in pain severity; n = 57, 44.2%) reported an overall improvement in psychological variables except alexithymia. Alexithymia showed relative stability between baseline and follow-up within the entire sample and remained a significant predictor of treatment outcome even when other predictive cofactors (i.e., pain interference, depressive symptoms, and catastrophizing) were considered simultaneously. Our results suggest that identifying patients with a co-occurrence between alexithymia, depressive symptoms, catastrophizing, and the stressful experience of chronic pain can be clinically relevant in pain prevention and intervention programs.

Non-operative management after immune checkpoint inhibitors for early-stage, dMMR/MSI-H gastrointestinal cancers.

Surgery is a standard treatment for early-stage gastrointestinal cancers, often preceded by neoadjuvant chemo(radio)therapy or followed by adjuvant therapy. While leading to cure in a proportion of patients, it has some drawbacks such as intra/post-operative complications, mutilation and life-long functional sequelae. Further to the unprecedented efficacy data from studies of immune checkpoint inhibitors for advanced mismatch repair deficient/microsatellite instable (dMMR/MSI-H) tumours, a strong interest has recently emerged for the investigation of such agents in the neoadjuvant setting. Although limited by the exploratory design and small sample size, trials of neoadjuvant immune checkpoint inhibitors for early-stage dMMR/MSI-H gastrointestinal cancers have consistently reported complete response rates ranging from 70 % to 100 %. As a result, the question has arisen as to whether surgery is still needed or organ-preserving strategies should be offered to this especially immuno-sensitive population. In this article, we discuss the available evidence for neoadjuvant immune checkpoint inhibitors in dMMR/MSI-H gastrointestinal cancers and analyse opportunities and challenges to the implementation of non-operative management approaches in this setting.

PD-L1 Expression in Paired Samples of Rectal Cancer.

Immune checkpoint inhibitors and immune-related biomarkers are increasingly investigated in rectal cancer (RC). We retrospectively analysed PD-L1 expression in diagnostic biopsy and resection samples from RC patients treated at our centre between 2000 and 2020. PD-L1 immunostaining (22C3 clone) was evaluated according to tumour proportion (TPS), immune cell (ICS), and the combined positive score (CPS). Eighty-three patients were included. At diagnosis, PD-L1 expression ≥1%/≥5% was observed in 15.4%/0%, 80.7%/37.4%, and 69.2%/25.6% of patients based on TPS, ICS, and CPS, respectively. At surgery, the respective figures were 4.6%/1.5%, 60.2%/32.5%, and 50.7%/26.2%. Using the 1% cut-off and regardless of the scoring system, PD-L1 was less expressed in surgery than biopsy samples (p ≤ 0.04). In paired specimens, PD-L1-ICS reduction was especially observed following neoadjuvant long-course (chemo)radiotherapy (p = 0.03). PD-L1-ICS of ≥5% in surgical samples (HR: 0.17; p = 0.02), and a biopsy-to-surgery increase in PD-L1-ICS (HR: 0.19; p = 0.04) was predictive for longer disease-free survival, while the PD-L1-ICS of either ≥1% (HR 0.28; p = 0.04) or ≥5% (HR 0.19; p = 0.03) in surgical samples and the biopsy-to-surgery increase in PD-L1-ICS (HR: 0.20; p = 0.04) were associated with better overall survival. Our study suggests that PD-L1 expression in RC is largely reflective of immune cell infiltration, and its presence/increase in surgical samples predicts better outcomes.

Alexithymia, suicide risk and serum lipid levels among adult outpatients with panic disorder.

To elucidate the relationships between alexithymia, suicide ideation and serum lipid levels in drug-naïve adult outpatients with a DSM-IV diagnosis of Panic Disorder (PD), 72 patients were evaluated. Measures were the Panic Attack and Anticipatory Anxiety Scale, the Toronto Alexithymia Scale (TAS-20), the Scale of Suicide Ideation (SSI) and the Montgomery Åsberg Depression Rating Scale (MADRS). Alexithymic patients showed higher scores on all rating scales and altered serum lipid levels than non-alexithymics. In the hierarchical regression model, the presence of lower HDL-C and higher VLDL-C levels and Difficulty in Identifying Feelings dimension of TAS-20 were associated with higher suicide ideation. In conclusion, alexithymic individuals with PD may show a cholesterol dysregulation that may be linked to suicide ideation. The authors discuss study limitations and future research needs.

Multi-Inflammatory Syndrome in Children (MIS-C) in 2023: Is It Time to Forget about It?

Multisystem inflammatory syndrome in children (MIS-C) is defined as a clinically serious condition requiring hospitalization involving fever, multi-system organ dysfunction, and an increase in inflammatory biomarkers. The syndrome was originally described as a post-infectious complication of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection, which usually causes COVID-19. During the COVID-19 pandemic, not only did the virus undergo mutations but vaccines against SARS-CoV-2 were also developed. Both these conditions led to a decrease in the incidence of MIS-C. This narrative review summarizes the recent updates for MIS-C, particularly regarding the change in incidence, the link between the SARS-CoV-2 vaccine and MIS-C, and new updates of MIS-C treatments.

Psychological correlates of perceived loneliness in college students before and during the COVID-19 stay-at-home period: a longitudinal study.

BACKGROUND: Loneliness is increasingly acknowledged as a serious public health issue. This longitudinal study aimed to assess the extent to which psychological distress and alexithymia can predict loneliness among Italian college students before and one year after the COVID-19 outbreak. METHODS: A convenience sample of 177 psychology college students were recruited. Loneliness (UCLA), alexithymia (TAS-20), anxiety symptoms (GAD-7), depressive symptoms (PHQ-9), and somatic symptoms (PHQ-15) were assessed before the COVID-19 outbreak and one year after the spread of COVID-19 worldwide. RESULTS: After controlling for baseline loneliness, students with high levels of loneliness during lockdown showed worsening psychological distress and alexithymic traits over time. Suffering from depressive symptoms before COVID-19 and the aggravation of alexithymic traits independently predicted 41% of perceived loneliness during the COVID-19 outbreak. CONCLUSIONS: College students with higher levels of depression and alexithymic traits both before and one year after the lockdown were more at risk of suffering from perceived loneliness and may constitute the target sample for psychological support and intervention.

Has the COVID-19 Pandemic Worsened Health-Related Quality of Life of Patients with Inflammatory Bowel Disease? A Longitudinal Disease Activity-Controlled Study.

The present longitudinal study aimed to investigate the burden of disease activity change on health-related quality of life (HRQoL) of patients with inflammatory bowel disease (IBD) during the two different pandemic waves in 2020 and 2021. A sample of 221 IBD patients (recruited during March-May 2020 for T0 and March-May 2021 for T1) was included. The psychological impact of the COVID-19 pandemic (Impact of Event Scale-Revised (IES-R)) and HRQoL (Inflammatory Bowel Disease Questionnaire (IBDQ)) were assessed. Post-traumatic COVID-19-related symptoms (IES-R) were not significantly different across the disease activity-related groups. Conversely, IBDQ was consistently higher in patients with persistent, quiescent disease activity compared to the other groups, as expected. Even after controlling for baseline IES-R, repeated-measures ANCOVA showed a non-significant main effect of time (p = 0.60) but a significant time-per-group interaction effect with a moderate effect size (η2 = 0.08). During the two different phases of pandemic restrictions, IBD-specific HRQoL was modified by disease-related factors such as disease activity, rather than by the post-traumatic symptoms of COVID-19. This lends further weight to the need for developing an evidence-based, integrated, biopsychosocial model of care for patients with IBD to identify subjective and objective factors that affect the burden of disease.

Changes in hospital staff' mental health during the Covid­19 pandemic: Longitudinal results from the international COPE-CORONA study.

This longitudinal study aimed to explore anxiety and depressive symptoms, individual resources, and job demands in a multi-country sample of 612 healthcare workers (HCWs) during the COVID-19 pandemic. Two online surveys were distributed to HCWs in seven countries (Germany, Andorra, Ireland, Spain, Italy, Romania, Iran) during the first (May-October 2020, T1) and the second (February-April 2021, T2) phase of the pandemic, assessing sociodemographic characteristics, contact with COVID-19 patients, anxiety and depressive symptoms, self-compassion, sense of coherence, social support, risk perception, and health and safety at the workplace. HCWs reported a significant increase in depressive and anxiety symptoms. HCWs with high depressive or anxiety symptoms at T1 and T2 reported a history of mental illness and lower self-compassion and sense of coherence over time. Risk perception, self-compassion, sense of coherence, and social support were strong independent predictors of depressive and anxiety symptoms at T2, even after controlling for baseline depressive or anxiety symptoms and sociodemographic variables. These findings pointed out that HCWs during the COVID-19 outbreak experienced a high burden of psychological distress. The mental health and resilience of HCWs should be supported during disease outbreaks by instituting workplace interventions for psychological support.