Negative symptoms and cognitive impairment are associated with distinct motivational deficits in treatment resistant schizophrenia.

BACKGROUND: Motivational deficits are a central feature of the negative syndrome in schizophrenia. They have consistently been associated with reduced willingness to expend physical effort in return for monetary rewards on effort based decision making (EBDM) paradigms. Nevertheless, the mechanisms underlying such altered performance are not well characterised, and it remains unclear if they are driven purely by negative symptoms, or also in part by cognitive impairment, antipsychotic treatment or even positive symptoms. Here we investigated the impact of all these factors using a paradigm that has not previously been used to measure EBDM in schizophrenia. METHODS: Forty treatment resistant schizophrenia (TRS) patients on clozapine and matched controls (N = 80) completed a well validated EBDM task which offers monetary rewards in return for physical effort. Choice and reaction time data was analysed using logistic regressions, as well as Bayesian hierarchical drift diffusion modelling (HDDM). Behavioural parameters were compared between groups and their association with negative symptoms, cognitive function and serum clozapine levels were assessed. RESULTS: Overall, TRS patients accepted significantly less offers than controls during effort-based decision making, suggesting they were less motivated. They demonstrated reduced sensitivity to increasing rewards, but surprisingly were also less averse to increasing effort. Despite a positive correlation between negative symptoms and cognitive function in TRS, reward sensitivity was associated only with cognitive performance. In contrast, reduced effort aversion correlated with negative symptom severity. Clozapine levels and positive symptoms were not associated with either behavioural parameter. CONCLUSION: Motivational deficits in TRS are characterised by both diminished reward sensitivity and reduced effort aversion during EBDM. Cognitive dysfunction and negative symptom severity account for distinct aspects of these behavioural changes, despite positive associations between themselves. Overall, these findings demonstrate that negative symptoms and cognitive impairment have significant independent contributions to EBDM in TRS, thereby opening the possibility of individualised treatment targeting these mechanisms to improve motivation.

Repurposing the oncolytic virus VSV∆51M as a COVID-19 vaccine.

The coronavirus disease 2019 (COVID-19) pandemic imposes an urgent and continued need for the development of safe and cost-effective vaccines to induce preventive responses for limiting major outbreaks around the world. To combat severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), we repurposed the VSV∆51M oncolytic virus platform to express the spike receptor-binding domain (RBD) antigen. In this study, we report the development and characterization of the VSV∆51M-RBD vaccine. Our findings demonstrate successful expression of the RBD gene by the VSV∆51M-RBD virus, inducing anti-RBD responses without attenuating the virus. Moreover, the VSV∆51M-RBD vaccine exhibited safety, immunogenicity, and the potential to serve as a safe and effective alternative or complementary platform to current COVID-19 vaccines.

Persistence of effort in apathy.

The syndrome of apathy has generated increasing interest in recent years as systematic evaluations have revealed its high prevalence and strong negative impact on quality of life across a wide range of neurological and psychiatric conditions. However, although several theoretical models have been proposed to account for various aspects of the condition, understanding of this syndrome is still incomplete. One influential model has proposed that apathy might be described as a quantitative reduction of goal-directed behaviour in comparison to an individual's prior level of functioning. Persistence of activity defined as the capacity to continue with a task - sometimes in the face of setbacks, high levels of difficulty or fatigue - is a crucial but understudied aspect of goal-directed behaviour. Surprisingly, it has not been investigated yet in the context of apathy. Here, we provide an overview of theoretical and experimental aspects of persistence in effort that might assist to develop methods for the investigation of persistence in human behaviour, particularly within the pathologic context of apathy.

Metabolically defined body size and body shape phenotypes and risk of postmenopausal breast cancer in the European Prospective Investigation into Cancer and Nutrition.

BACKGROUND: Excess body fatness and hyperinsulinemia are both associated with an increased risk of postmenopausal breast cancer. However, whether women with high body fatness but normal insulin levels or those with normal body fatness and high levels of insulin are at elevated risk of breast cancer is not known. We investigated the associations of metabolically defined body size and shape phenotypes with the risk of postmenopausal breast cancer in a nested case-control study within the European Prospective Investigation into Cancer and Nutrition. METHODS: Concentrations of C-peptide-a marker for insulin secretion-were measured at inclusion prior to cancer diagnosis in serum from 610 incident postmenopausal breast cancer cases and 1130 matched controls. C-peptide concentrations among the control participants were used to define metabolically healthy (MH; in first tertile) and metabolically unhealthy (MU; >1st tertile) status. We created four metabolic health/body size phenotype categories by combining the metabolic health definitions with normal weight (NW; BMI < 25 kg/m2 , or WC < 80 cm, or WHR < 0.8) and overweight or obese (OW/OB; BMI ≥ 25 kg/m2 , or WC ≥ 80 cm, or WHR ≥ 0.8) status for each of the three anthropometric measures separately: (1) MHNW, (2) MHOW/OB, (3) MUNW, and (4) MUOW/OB. Conditional logistic regression was used to compute odds ratios (ORs) and 95% confidence intervals (CIs). RESULTS: Women classified as MUOW/OB were at higher risk of postmenopausal breast cancer compared to MHNW women considering BMI (OR = 1.58, 95% CI = 1.14-2.19) and WC (OR = 1.51, 95% CI = 1.09-2.08) cut points and there was also a suggestive increased risk for the WHR (OR = 1.29, 95% CI = 0.94-1.77) definition. Conversely, women with the MHOW/OB and MUNW were not at statistically significant elevated risk of postmenopausal breast cancer risk compared to MHNW women. CONCLUSION: These findings suggest that being overweight or obese and metabolically unhealthy raises risk of postmenopausal breast cancer while overweight or obese women with normal insulin levels are not at higher risk. Additional research should consider the combined utility of anthropometric measures with metabolic parameters in predicting breast cancer risk.

Correction: A Cross-Sectional Study of the Knowledge, Attitude, and Practice of Self-Medication Among the General Population in the Western Region of Saudi Arabia.

[This corrects the article DOI: 10.7759/cureus.29944.].

Gut inflammation and adaptive immunity amplify acetaminophen toxicity in bowel and liver.

BACKGROUND AND AIM: Prevention of liver failure arising from accidental or deliberate paracetamol (acetaminophen [APAP]) overdose remains a vexed health problem despite well-publicized guidelines for its early detection and treatment. It is recognized that the gut may aggravate liver pathology, via the gut-liver axis. The main aim of this study was to assess the role of the colon in APAP-induced liver toxicity. METHODS: Liver necrosis and colitis were studied following sublethal doses of APAP administered intraperitoneally to C57Bl/6 wild-type (WT) mice, as well as to C57Bl/6 Winnie mice, which develop a spontaneous colitis caused by a SNP in Muc2, and WT mice with acute DSS-induced colitis. Repeated APAP exposure was studied in WT and Rag1 ko mice that lack mature T and B lymphocytes. RESULTS: APAP overdose resulted in significant colonic injury in WT mice (P < 0.05), which resolved by 24 h. Underlying colitis was not associated with liver necrosis, but colitis exacerbated APAP-induced liver injury and extended APAP-colonic injury. Prior APAP exposure exacerbated both APAP-liver and APAP-colonic injury more so in WT than Rag1 ko mice. APAP impaired barrier function with increased intestinal permeability and associated bacterial translocation to the liver and spleen in mice with the Winnie phenotype. CONCLUSIONS: This study identifies novel roles for APAP in causing colitis, the amplification of APAP-liver toxicity where there is underlying colitis, and involvement of immune memory in APAP-toxicity. The latter could be key for decoding the poorly understood but important clinical entity of chronic APAP liver failure.

Awareness and Practice of Najran University Students Towards Common Problems Related to Ear, Nose, and Throat.

OBJECTIVE:  The objective of this study was to evaluate the awareness and practice of Najran University students toward common problems related to the ear, nose, and throat. METHODS:  A cross-sectional study was utilized in this research, employing data from a sample of 429 students at Najran University. The participants completed a self-administered questionnaire and ensured anonymity. The questionnaire used in this study had been previously validated. RESULTS:  The sample for the current study primarily consisted of students aged more than 20 years (84.1%; n = 361), with a predominance of females (69.0%; n = 296). The majority of them were in health colleges (45.2%; n=194). The study results show that 37.8% (n = 162) had a good knowledge level, while 62.2% (n = 267) had poor knowledge about problems related to ENT. The vast majority, 87.2% (n = 374), believed that going to the hospital was the appropriate action to take in cases of acute ENT problems. The results established a statistically significant association between age, gender, health college, college, and department with p-values <0.005 (0.002*, 0.001*, 0.003*, and 0.005*), respectively, and the level of knowledge about problems related to ENT. There was no statistically significant association between nationality, clinical history of the participants, and the level of knowledge about problems related to ENT (p > 0.005). CONCLUSION:  The study revealed that 37.8% of the participants had good knowledge about problems related to the ears, nose, and throat. The participants older than 20 years had better knowledge of common ENT problems than those younger than 20 years. Female participants showed a higher level of knowledge and awareness of problems related to the ears, nose, and throat. The study noted that the participants in Health College, the faculty of medicine, and the third academic level had good knowledge about problems related to ENT. The study established that going to the hospital was the appropriate action to be taken in case of a sudden ENT problem. Therefore, we recommend concerted efforts be made among the medical community to increase knowledge about common ENT problems.

A Cross-Sectional Study of the Knowledge, Attitude, and Practice of Self-Medication Among the General Population in the Western Region of Saudi Arabia.

Introduction Self-medication (SM) is defined as consuming pharmaceutical drugs without the advice of a physician for either diagnosis or treatment. Reliance on self-medication has become a more common worldwide issue and now plays a major role in self-care. However, the practice is linked to many risks for patients and the whole community. This study assesses knowledge, attitudes, and practices associated with self-medication in the western region of Saudi Arabia. Methods This is an observational questionnaire-based cross-sectional study conducted over two months, between January and March 2022. The survey comprised 29 questions adapted from similar studies and was translated into Arabic to fit the study population. All residents of the three major cities, Makkah, Jeddah, and Taif, were included; the population under 18 years of age and health workers were excluded. We used OpenEpi version 3.0 (www.OpenEpi.com) for sample size calculation and Statistical Package for Social Sciences (IBM Corp, Armonk, USA) was used for data analysis. Results Most of the participants (67.7%) declared that they practiced self-medication: (28.6%) men and (39.1%) women. Self-medicating for different indications showed differences between men and women but without statistical significance. Major indications for self-medicating were headache (45.3%), cough, cold/flu (42.7%), and fever (34.0%). The primary reasons participants gave for choosing to self-medicate were easy availability of the medicines (41.4%) and that they were treating a minor illness (40.8%). Many types of medicines were used, most commonly analgesics (44.0%) and antipyretics (43.6%). Conclusion The practice of self-medication is high among the population in Makkah, Jeddah, and Taif. Educating the public on the consequences and adverse effects is necessary.

Organic optoelectronic copolymer involving PVK and F8T2: Synthesis and characterization.

The synthesis of new fluorescent polymers based on π-conjugated chains is a major challenge for organic electronic. The materials must be soluble, stable over long periods and able to be produced with a high yield. In particular, poly (vinylcarbazole), poly (fluorenes), and poly (thiophene) partially meet these criteria. In this study, new soluble copolymers PVK-F8T2 was synthesized from poly(9-vinylcarbazole) (PVK) and poly[(9,9-dioctylfluorenyl-2,7-diyl)-co-(bithiophène)] (F8T2). As these materials are highly luminescent and green-emitting, they have good chemical and thermal stability and can be easily functionalized. Here, the vibrational and optical properties of PVK-F8T2 was studied using several different techniques, including Infrared absorption, Raman scattering, thermogravimetric analysis (TGA), UV-visible optical absorption, and both stationary and transient photoluminescence. The novel copolymer shows an increase of thermal stability compared to the two original polymers (PVK and F8T2). The stationary and transient photoluminescence reveal an energy transfer from PVK to F8T2. This study indicates that these copolymers are good candidates for photophysical applications.

Mesenteric cystic lymphangioma: A case report.

INTRODUCTION AND IMPORTANCE: Mesenteric cystic lymphangiomas are rare benign lesions of the abdominal cavity characterized by lymphatic vessels malformation with an unknown etiology. Despite the silent clinical course of mesenteric cystic lymphangiomas, they are considered as clinically tricky lesions with an immense spectrum of presentations. CASE PRESENTATION: We present a case of abdominal mesenteric cystic lymphangioma in a 1-year 9-month-old female patient, who complained of fever and abdominal pain for 10 days duration. Laboratory investigations, abdominal X-ray, ultrasonography, computed tomography and histopathological examination were all used to establish the diagnosis. CLINICAL DISCUSSION: A trial of true-cut biopsies performed by an interventional radiologist was not informative, so a multidisciplinary team decision was made to excise the mass. Intraoperative findings include multiloculated fused cystic lesion (8.0 × 5.0 × 4.0 cm) on the descending mesocolon. Histopathological examination revealed the diagnosis of a mesenteric cystic lymphangioma. The postoperative period was not complicated. CONCLUSION: Mesenteric cystic lymphangiomas are mostly asymptomatic in nature, yet predisposed to life threating events. Surgical excision is the modality of treatment characterized by low recurrence rate and a non-complicated postoperative period.

Study of in vitro and in vivo genotoxic effects of air pollution fine (PM2.5-0.18) and quasi-ultrafine (PM0.18) particles on lung models.

Air pollution and particulate matter (PM) are classified as carcinogenic to humans. Pollutants evidence for public health concern include coarse (PM10) and fine (PM2.5) particles. However, ultrafine particles (PM0.1) are assumed to be more toxic than larger particles, but data are still needed to better understand their mechanism of action. In this context, the aim of our work was to investigate the in vitro and in vivo genotoxic potential of fine (PM2.5-018) and quasi ultra-fine (PM0.18) particles from an urban-industrial area (Dunkirk, France) by using comet, micronucleus and/or gene mutation assays. In vitro assessment was performed with 2 lung immortalized cell lines (BEAS-2B and NCI-H292) and primary normal human bronchial epithelial cells (NHBE) grown at the air-liquid interface or in submerged conditions (5 µg PM/cm2). For in vivo assessment, tests were performed after acute (24 h, 100 µg PM/animal), subacute (1 month, 10 µg PM/animal) and subchronic (3 months, 10 µg PM/animal) intranasal exposure of BALB/c mice. In vitro, our results show that PM2.5-018 and PM0.18 induced primary DNA damage but no chromosomal aberrations in immortalized cells. Negative results were noted in primary cells for both endpoints. In vivo assays revealed that PM2.5-018 and PM0.18 induced no significant increases in DNA primary damage, chromosomal aberrations or gene mutations, whatever the duration of exposure. This investigation provides initial answers regarding the in vitro and in vivo genotoxic mode of action of PM2.5-018 and PM0.18 at moderate doses and highlights the need to develop standardized specific methodologies for assessing the genotoxicity of PM. Moreover, other mechanisms possibly implicated in pulmonary carcinogenesis, e.g. epigenetics, should be investigated.

Body mass index, abdominal fatness, weight gain and the risk of urinary incontinence: a systematic review and dose-response meta-analysis of prospective studies.

BACKGROUND: Adiposity has been associated with elevated risk of urinary incontinence in epidemiological studies; however, the strength of the association has differed between studies. OBJECTIVES: To conduct a systematic literature review and dose-response meta-analysis of prospective studies on adiposity and risk of urinary incontinence. SEARCH STRATEGY: We searched PubMed and Embase databases up to 19 July 2017. SELECTION CRITERIA: Prospective cohort studies were included. DATA COLLECTION AND ANALYSIS: Data were extracted by one reviewer and checked for accuracy by a second reviewer. Summary relative risks (RRs) and 95% confidence intervals (CIs) were calculated using random effects models. MAIN RESULTS: Twenty-four prospective studies were included. The summary RR per 5 kg/m2 increment in body mass index (BMI) was 1.20 (95% CI 1.16-1.25, I2  = 62%, n = 11) for population-based studies and 1.19 (95% CI 1.08-1.30, I2  = 87.1%, n = 8) for pregnancy-based studies, 1.18 (95% CI 1.14-1.22, I2  = 0%, n = 2) per 10 cm increase in waist circumference and 1.34 (95% CI 1.11-1.62, I2  = 90%, n = 2) per 10 kg of weight gain. Although the test for nonlinearity was significant for BMI, P = 0.04, the association was approximately linear. For subtypes of urinary incontinence the summary RR per 5 BMI units was 1.45 (95% CI 1.25-1.68, I2  = 85%, n = 3) for frequent incontinence, 1.52 (95% CI 1.37-1.68, I2  = 34%, n = 4) for severe incontinence, 1.33 (95% CI 1.26-1.41, I2  = 0%, n = 8) for stress incontinence, 1.26 (95% CI 1.14-1.40, I2  = 70%, n = 7) for urge incontinence, and 1.52 (95% CI 1.36-1.69, I2  = 0%, n = 3) for mixed incontinence. CONCLUSION: These results suggest excess weight may increase risk of urinary incontinence. TWEETABLE ABSTRACT: Overweight and obesity increase the risk of urinary incontinence.

Toxicological effects of ambient fine (PM2.5-0.18) and ultrafine (PM0.18) particles in healthy and diseased 3D organo-typic mucocilary-phenotype models.

The knowledge of the underlying mechanisms by which particulate matter (PM) exerts its health effects is still incomplete since it may trigger various symptoms as some persons may be more susceptible than others. Detailed studies realized in more relevant in vitro models are highly needed. Healthy normal human bronchial epithelial (NHBE), asthma-diseased human bronchial epithelial (DHBE), and COPD-DHBE cells, differentiated at the air-liquid interface, were acutely or repeatedly exposed to fine (i.e., PM2.5-0.18, also called FP) and quasi-ultrafine (i.e., PM0.18, also called UFP) particles. Immunofluorescence labelling of pan-cytokeratin, MUC5AC, and ZO-1 confirmed their specific cell-types. Baselines of the inflammatory mediators secreted by all the cells were quite similar. Slight changes of TNFα, IL-1ß, IL-6, IL-8, GM-CSF, MCP-1, and/or TGFα, and of H3K9 histone acetylation supported a higher inflammatory response of asthma- and especially COPD-DHBE cells, after exposure to FP and especially UFP. At baseline, 35 differentially expressed genes (DEG) in asthma-DHBE, and 23 DEG in COPD-DHBE, compared to NHBE cells, were reported. They were involved in biological processes implicated in the development of asthma and COPD diseases, such as cellular process (e.g., PLA2G4C, NLRP1, S100A5, MUC1), biological regulation (e.g., CCNE1), developmental process (e.g., WNT10B), and cell component organization and synthesis (e.g., KRT34, COL6A1, COL6A2). In all the FP or UFP-exposed cell models, DEG were also functionally annotated to the chemical metabolic process (e.g., CYP1A1, CYP1B1, CYP1A2) and inflammatory response (e.g., EREG). Another DEG, FGF-1, was only down-regulated in asthma and specially COPD-DHBE cells repeatedly exposed. While RAB37 could help to counteract the down-regulation of FGF-1 in asthma-DHBE cells, the deregulation of FGR, WNT7B, VIPR1, and PPARGC1A could dramatically contribute to make it worse in COPD-DHBE cells. Taken together, these data contributed to support the highest effects of UFP versus FP and highest sensitivity of asthma- and notably COPD-DHBE versus NHBE cells.

Postmenopausal hormone use and cutaneous melanoma risk: A French prospective cohort study.

Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between menopausal hormone therapy (MHT) use and melanoma risk; however, previous findings were conflicting. We sought to explore the associations between MHT use and melanoma risk in a prospective cohort of women in France, where a particularly wide variety of MHT formulations are available. E3N is a prospective cohort of 98,995 French women aged 40-65 years in 1990. MHT use was assessed through biennial self-administered questionnaires. We used Cox proportional hazards regression models adjusted for age and skin cancer risk factors. Over 1990-2008, 444 melanoma cases were ascertained among 75,523 postmenopausal women. Ever use of MHT was associated with a higher melanoma risk (hazard ratio (HR) = 1.35, 95% confidence intervals (CI) = 1.07-1.71). The association was strongest among past users (HR = 1.55, CI = 1.17-2.07, homogeneity for past vs. recent use: p = 0.11), and users of MHT containing norpregnane derivatives (HR = 1.59, CI = 1.11-2.27), although with no heterogeneity across types of MHT (p = 0.13). Among MHT users, the association was similar across durations of use. However, a higher risk was observed when treatment onset occurred shortly after menopause (<6 months: HR = 1.55, CI = 1.16-2.07 vs. ≥2 years). Associations between MHT use and melanoma risk were similar after adjustment for UV exposure, although MHT users were more likely to report sunscreen use than nonusers. Our data do not support a strong association between MHT use and melanoma risk. Further investigation is needed to explore potential effect modification by UV exposure on this relationship.

Oral contraceptive use and cutaneous melanoma risk: a French prospective cohort study.

Cutaneous melanoma has been suspected to be influenced by female hormones. Several studies reported a positive association between oral contraceptive (OC) use and melanoma risk. However, findings were conflicting and data from large prospective studies are lacking. E3N is a prospective cohort of 98,995 French women aged 40-65 years at inclusion in 1990. Exposure to lifetime OC use was assessed in 1992 and through biennial questionnaire updates. To assess the association between OC use and melanoma risk, we used Cox models adjusted for age, pigmentary traits, residential ultraviolet (UV) exposure in county of birth and at inclusion and family history of skin cancer. Over 1992-2008, 539 melanoma cases were ascertained among 79,365 women. In age-adjusted models, we found a modest positive association between ever use of OCs and melanoma risk (hazard ratio (HR) = 1.18, 95% confidence intervals (CIs) = 0.98-1.42), which was reduced after adjustment (HR = 1.14, 95% CI = 0.95-1.38). The association was stronger in long-term users (duration ≥10 years: HR = 1.33, 95% CI = 1.00-1.75) and in women who used high-estrogen OCs (HR = 1.27, 95% CI = 1.04-1.56). Among users, there was an inverse association with age at first use (ptrend < 0.01), but no evidence of an association with age at last use or time since last use. OC use was positively associated with tanning bed use (OR = 1.14, CI = 1.01-1.29), sunburns (ptrend = 0.5) and sunscreen use (OR = 1.13, CI = 1.00-1.28) since age 25. Overall, our findings do not support a strong association between OC use and melanoma risk and suggest intentional UV exposure in OC users, which supports a potential confusion by UV exposure in this relationship.

The role of IL-22 in the resolution of sterile and nonsterile inflammation.

In a broad sense, inflammation can be conveniently characterised by two phases: the first phase, which is a pro-inflammatory, has evolved to clear infection and/or injured tissue; and the second phase concerns regeneration of normal tissue and restitution of normal physiology. Innate immune cell-derived pro-inflammatory cytokines and chemokines activate and recruit nonresident immune cells to the site of infection, thereby amplifying the inflammatory responses to clear infection or injury. This phase is followed by a cytokine milieu that promotes tissue regeneration. There is no absolute temporal distinction between these two phases, and cytokines may have dual pleiotropic effects depending on the timing of release, inflammatory microenvironment or concentrations. IL-22 is a cytokine with reported pro- and anti-inflammatory roles; in this review, we contend that this protein has primarily a function in restitution of normal tissue and physiology.