The dopamine D1 receptor positive allosteric modulator, DETQ, improves cognition and social interaction in aged mice and enhances cortical and hippocampal acetylcholine efflux.

Dopamine (DA) D1 and D2 receptors (Rs) are critical for cognitive functioning. D1 positive allosteric modulators (D1PAMs) activate D1Rs without desensitization or an inverted U-shaped dose response curve. DETQ, [2-(2,6-dichlorophenyl)-1-((1S,3R)-3-(hydroxymethyl)-5-(2-hydroxypropan-2-yl)-1-methyl-3,4-dihydroisoquinolin-2(1H)-yl)ethan-1-one] is highly selective for the human D1Rs as shown in humanized D1R knock-in (hD1Ki) mice. Here, we have ascertained the efficacy of DETQ in aged [13-23-month-old (mo)] hD1Ki mice and their corresponding age-matched wild-type (WT; C57BL/6NTac) controls. We found that in aged mice, DETQ, given acutely, subchronically, and chronically, rescued both novel object recognition memory and social behaviors, using novel object recognition (NOR) and social interaction (SI) tasks, respectively without any adverse effect on body weight or mortality. We have also shown, using in vivo microdialysis, a significant decrease in basal DA and norepinephrine, increase in glutamate (Glu) and gamma-amino butyric acid (GABA) efflux with no significant changes in acetylcholine (ACh) levels in aged vs young mice. In young and aged hD1Ki mice, DETQ, acutely and subchronically increased ACh in the medial prefrontal cortex and hippocampal regions in aged hD1Ki mice without affecting Glu. These results suggest that the D1PAM mechanism is of interest as potential treatment for cognitive and social behavioral deficits in neuropsychiatric disorders including but not restricted to neurodegenerative disorders, such as Parkinson's disease.

NU-1223, a simplified analog of alstonine, with 5-HT2cR agonist-like activity, rescues memory deficit and positive and negative symptoms in subchronic phencyclidine mouse model of schizophrenia.

The serotonin (5-HT)2 C receptor(R) is a widely distributed G-protein-coupled receptor, expressed abundantly in the central nervous system. Alstonine is a natural product that has significant properties of atypical antipsychotic drugs (AAPDs), in part attributed to 5-HT2 CR agonism. Based on alstonine, we developed NU-1223, a simplified ß carboline analog of alstonine, which shows efficacies comparable to alstonine and to other 5-HT2 CR agonists, Ro-60-0175 and lorcaserin. The 5-HT2 CR antagonism of some APDs, including olanzapine, contributes to weight gain, a major side effect which limits its tolerability, while the 5-HT2 CR agonists and/or modulators, may minimize weight gain. We used the well-established rodent subchronic phencyclidine (PCP) model to test the efficacy of NU-1223 on episodic memory, using novel object recognition (NOR) task, positive (locomotor activity), and negative symptoms (social interaction) of schizophrenia (SCH). We found that NU-1223 produced both transient and prolonged rescue of the subchronic PCP-induced deficits in NOR and SI. Further, NU-1223, but not Ro-60-0175, blocked PCP and amphetamine (AMPH)-induced increase in LMA in subchronic PCP mice. These transient efficacies in LMA were blocked by the 5-HT2 CR antagonist, SB242084. Sub-chronic NU-1223 treatment rescued NOR and SI deficits in subchronic PCP mice for at least 39 days after 3 days injection. Chronic treatment with NU-1223, ip, twice a day for 21 days, did not increase average body weight vs olanzapine. These findings clearly indicate NU-1223 as a class of small molecules with a possible 5-HT2 CR-agonist-like mechanism of action, attributing to its efficacy. Additional in-depth receptor mechanistic studies are warranted, as this small molecule, both transiently and chronically rescued PCP-induced deficits. Furthermore, NU-1223 did not induce weight gain post long-term administrations vs AAPDs such as olanzapine, making NU-1223 a putative therapeutic compound for SCH.

Chlamydia pneumonia infection and risk of multiple sclerosis: A meta-analysis.

BACKGROUND: The role of infectious agents, including Chlamydia pneumoniae (Cpn), in the development of multiple sclerosis (MS), is still a matter of major contention. OBJECTIVE: This meta-analysis study aimed to assess the actual involvement of Cpn in MS development. METHODS: We undertook a search of international scientific databases to identify eligible studies. We used a random-effects meta-analysis model (REM) to generate the pooled odds ratio (OR) and 95% confidence intervals (CIs). Heterogeneity was calculated using the I2 statistic. Sensitivity and subgroup analyses were applied to assess the effects of study characteristics and socio-demographic variables on the pooled OR. RESULTS: We identified 37 studies comprising 51 datasets that satisfied the inclusion criteria. Considering diagnostic methods for Cpn, 26 and 25 datasets used PCR- and serological-based methods, respectively. In PCR-based datasets, REM showed a significant positive association between Cpn infection and the development of MS (OR, 5.29; 95% CI, 3.12-8.97), while a non-significant positive association was achieved in serological-based datasets (OR, 1.34; 95% CI, 0.88-2.03). In subgroup analyses on PCR-based datasets, results were significant for both CSF (OR, 5.70) and serum (OR, 4.84) samples; both healthy (OR, 16.11) and hospital-based (OR, 2.88) controls; and both moderate (OR, 5.14) and high (OR, 5.48) quality studies. In serological-based datasets, only those that used CSF samples yielded significant results (OR, 3.41). CONCLUSIONS: Our findings verify the significant positive relationship between Cpn infection and MS. We advocate prospective cohort studies with lifelong follow-ups and also experimental studies to better understand the role of Cpn in MS development.

SARS-CoV-2 seroprevalence in children worldwide: A systematic review and meta-analysis.

Background: The higher hospitalisation rates of those aged 0-19 years (referred to herein as 'children') observed since the emergence of the immune-evasive SARS-CoV-2 Omicron variant and subvariants, along with the persisting vaccination disparities highlighted a need for in-depth knowledge of SARS-CoV-2 sero-epidemiology in children. Here, we conducted this systematic review to assess SARS-CoV-2 seroprevalence and determinants in children worldwide. Methods: In this systematic review and meta-analysis study, we searched international and preprinted scientific databases from December 1, 2019 to July 10, 2022. Pooled seroprevalences were estimated according to World Health Organization (WHO) regions (at 95% confidence intervals, CIs) using random-effects meta-analyses. Associations with SARS-CoV-2 seroprevalence and sources of heterogeneity were investigated using sub-group and meta-regression analyses. The protocol used in this study has been registered in PROSPERO (CRD42022350833). Findings: We included 247 studies involving 757,075 children from 70 countries. Seroprevalence estimates varied from 7.3% (5.8-9.1%) in the first wave of the COVID-19 pandemic to 37.6% (18.1-59.4%) in the fifth wave and 56.6% (52.8-60.5%) in the sixth wave. The highest seroprevalences in different pandemic waves were estimated for South-East Asia (17.9-81.8%) and African (17.2-66.1%) regions; while the lowest seroprevalence was estimated for the Western Pacific region (0.01-1.01%). Seroprevalence estimates were higher in children at older ages, in those living in underprivileged countries or regions, and in those of minority ethnic backgrounds. Interpretation: Our findings indicate that, by the end of 2021 and before the Omicron wave, around 50-70% of children globally were still susceptible to SARS-CoV-2 infection, clearly emphasising the need for more effective vaccines and better vaccination coverage among children and adolescents, particularly in developing countries and minority ethnic groups. Funding: None.

Worldwide prevalence of human papillomavirus among pregnant women: A systematic review and meta-analysis.

Human papillomavirus (HPV) is the causative agent of cervical cancer and a suspected agent for ovarian and endometrial cancers in women. It is associated with adverse outcomes during pregnancy. To date, there is no estimate of the prevalence of HPV infection in pregnant women at the regional and global levels. This study evaluated the global prevalence of HPV infection based on all observational studies that had reported the prevalence of HPV among pregnant women between January 1980 and December 2021 in PubMed/MEDLINE, Scopus, Web of Science, Embase, and SciELO databases. We utilised a random-effect model to determine the global prevalence and related risk factors of HPV infection. Between-studies heterogeneity was assessed using I2 statistic. Moreover, subgroup and meta-regression analyses were employed to assess the source of heterogeneity and the relationship between HPV prevalence and socio-demographic factors, respectively. Among 144 eligible studies comprising 189 datasets, the overall prevalence rates of HPV at the 95% confidence interval (CI) were estimated as 30.38% (26.88%-33.99%), 17.81% (9.81%-27.46%), 32.1% (25.09%-39.67%), 2.26% (0.1%-8.08%) and 25.5% (23.3%-27.8%) in cervico-vaginal, placenta, serum, amniotic fluid and urine samples, respectively. The highest prevalence rates were estimated for countries in the African region, while countries in the European and Eastern Mediterranean regions showed the lowest prevalence rates. HPV-16 and -18 were the most prevalent isolated strains. The pregnant women living with HIV and those with pregnancy disorders had significantly higher prevalence rates than general pregnant women (p < 0.05). The younger ages for first intercourse and pregnancy, multiple lifetime sexual partners, and lower education levels were primary risk factors for HPV infection. In conclusion, although the overall HPV prevalence varied markedly based on sampling sites and geographical locations, the highest prevalence rates were observed in less-developed countries. Our findings imply that implementing behavioural and therapeutic interventions as well as vaccination programs are crucial to prevent and reduce the current burden of HPV infection among pregnant women.

Global prevalence of Neisseria gonorrhoeae infection in pregnant women: a systematic review and meta-analysis.

BACKGROUND: Neisseria gonorrhoeae infection (gonorrhoea) is associated with several pregnancy complications, including preterm labour, spontaneous abortion, stillbirth, miscarriage, growth retardation, and intrauterine death. OBJECTIVES: We performed a systematic review and meta-analysis to estimate the global and regional prevalence of gonorrhoea in pregnant women as a scientific basis for further studies. DATA SOURCES: We systematically searched PubMed/MEDLINE, Web of Science, Embase, Scopus, and SciELO databases from inception to 10 July 2022. STUDY ELIGIBILITY CRITERIA: We included cross-sectional, cohort, and case-control studies that reported the prevalence of gonorrhoea in pregnant women. In addition, we included baseline data for randomized controlled trials. PARTICIPANTS: Pregnant women who were tested for gonorrhoea. METHODS: Pooled prevalence estimates at 95% CIs were calculated using a random-effects meta-analysis model. We stratified countries according to WHO-defined regions and socio-economic factors. Moreover, sub-group-, meta-regression, and sensitivity analyses were conducted to investigate the effects of pre-determined factors on prevalence estimates and heterogeneity. RESULTS: We identified 235 studies (249 datasets) on 19 104 175 pregnant women from 71 countries. The worldwide pooled prevalence of gonorrhoea in pregnant women was estimated at 1.85% (95% CI 1.73-1.97%), with the highest rate in the African region (3.53%) (2.84-4.29%) and the lowest rate in the European region (0.52%) (0.27-0.84%). Overall, the prevalence estimates were high among low-income countries (3.03%), pregnant women with HIV (2.81%), and pregnant women <20 years old (8.06%). A significant decreasing trend in prevalence was observed over time (ß = -0.0008, 95% CI -0.0012 to -0.0004, p 0.001). DISCUSSION: Our findings indicate that a substantial number of pregnant women have been infected with gonorrhoea globally, which calls for immediate public health measures to reduce the potential risk of infection. The study highlights the inadequacy or lack of data for many countries, emphasizing the need to expand systematic data collection efforts at national and regional levels.

Global prevalence of Ascaris infection in humans (2010-2021): a systematic review and meta-analysis.

BACKGROUND: Ascariasis is one of the most important neglected tropical diseases of humans worldwide. The epidemiology of Ascaris infection appears to have changed with improvements in sanitation and mass drug administration, but there is no recent information on prevalence worldwide. Here, we performed a systematic review and meta-analysis to assess the global prevalence of human Ascaris infection from 2010 to 2021. METHODS: We searched MEDLINE/PubMed, and Scopus databases for studies measuring prevalence of Ascaris infection, published between 1 January 2010 and 1 January 2022. We included studies of the general human population in endemic regions, which used accepted coprodiagnostic methods, and excluded studies of people with occupations with an increased risk or probability of ascariasis and/or specific diseases other than ascariasis. We applied random-effects models to obtain pooled prevalence estimates for six sustainable development goal regions of the world. We extrapolated the prevalence estimates to the global population in 2020, to estimate the number of individuals with Ascaris infection. We conducted multiple subgroup and meta-regression analyses to explore possible sources of heterogeneity, and to assess relationships between prevalence estimates and demographic, socio-economic, geo-climatic factors. RESULTS: Of 11,245 studies screened, we analysed 758 prevalence estimates for a total number of 4,923,876 participants in 616 studies from 81 countries. The global prevalence estimated was 11.01% (95% confidence interval: 10.27-11.78%), with regional prevalences ranging from 28.77% (7.07-57.66%) in Melanesia (Oceania) to 1.39% (1.07-1.74%) in Eastern Asia. We estimated that ~ 732 (682-782) million people harboured Ascaris worldwide in 2021. The infected people in Latin America and the Caribbean region had a higher prevalence of high intensity infection (8.4%, 3.9-14.1%). Prevalence estimates were higher in children, and people in rural communities or in countries or regions with lower income and human development indices. There was a trend for a higher prevalence in regions with increasing mean annual relative humidity, precipitation and environmental temperature. CONCLUSIONS: Our findings indicate that, despite a renewed commitment by some communities or authorities to control ascariasis, a substantial portion of the world's human population (> 0.7 billion) is infected with Ascaris. Despite the clinical and socioeconomic importance of ascariasis, many past routine surveys did not assess the intensity of Ascaris infection in people. We propose that the present findings might stimulate the development of customised strategies for the improved control and prevention of Ascaris infection worldwide.

Helicobacter pylori infection and risk of multiple sclerosis: An updated meta-analysis.

BACKGROUND: There is considerable controversy around the question as to whether Helicobacter pylori (H. pylori) infection has a protective or causative role in the development of multiple sclerosis (MS). This study evaluated published information to assess the association between H. pylori infection and MS. METHODS: We conducted a comprehensive systematic review of relevant observational studies in international databases. A random-effects model was used to calculate pooled odds ratio (OR) and 95% confidence interval (CI). I2 statistic was used to assess the between-study heterogeneity. Subgroup and meta-regression analyses were applied to identify the source of heterogeneity. RESULTS: In total, 22 studies (25 datasets) were eligible for the meta-analysis: 17 datasets had prevalence data and eight datasets had data on the mean titer of anti-H. pylori IgG. The pooled prevalence of H. pylori was 44.1% (908/2606) in the MS patients and 46.1% (1016/2200) in the controls, indicating a non-significant protective effect of H. pylori on MS (OR, 0.82; 95%CI, 0.58-1.17). In the subgroup analysis, studies that used ELISA yielded a significant protective association (OR, 0.59; 95%CI, 0.46-0.77), while a positive non-significant association (OR, 1.33; 95%CI, 0.83-2.15) was found from studies that used other serological methods; interestingly, a significant positive association (OR, 6.64; 95%CI, 2.40-13.76) was found from studies that used histological methods to detect H. pylori infection. CONCLUSIONS: Our findings do not support the hypothesis that H. pylori infection represents a protective factor against the development of MS; however, the results varied depending on the diagnostic method(s). Particularly, a significant positive association was identified when studies introduced results based on histological examination, suggesting that active H. pylori infection might be a risk factor for development of MS. Thus, further studies are needed utilizing accurate diagnostic methods to elucidate the association between active H. pylori infection and MS.

Does latent Toxoplasma infection have a protective effect against developing multiple sclerosis? Evidence from an updated meta-analysis.

Previous epidemiologic evidence suggests a protective effect of Toxoplasma gondii infection against multiple sclerosis (MS) development; however, inconsistent findings have been reported in this regard. Therefore, we performed an updated meta-analysis of observational studies to investigate the association of To. gondii infection with MS development. We searched all articles published in PubMed, Scopus, Embase and Web of Science databases as of 20 December 2021. A random effects meta-analysis model was used to generate the pooled OR at 95% CIs. The heterogeneity between studies was assessed using I2 and Cochran's Q statistics. Moreover, the likelihood of publication bias was determined by Egger's regression test. A total of 11 studies were eligible for meta-analysis, including 1172 MS cases and 1802 controls. Our findings indicated that 29.8% (95% CI 22.8 to 37.2%) of MS patients were seropositive for To. gondii infection, compared with 34.2% (95% CI 21.9 to 47.6%) of control subjects. The estimated pooled OR was 0.79 (95% CI 0.49 to 1.26), suggesting a non-significant negative association between To. gondii infection and MS development (p>0.05). The current study does not support the significant protective role of To. gondii infection on MS development. Our findings imply that further well-designed epidemiological and mechanistic studies are warranted to ascertain the possible association between To. gondii infection and MS and to exclude the potential confounders.

The neglected role of Blastocystis sp. and Giardia lamblia in development of irritable bowel syndrome: A systematic review and meta-analysis.

The possible role of Blastocystis sp. and Giardia lamblia infections in the development of irritable bowel syndrome (IBS) has long been controversial. In this study, we conducted a systematic review and meta-analysis to investigate whether these protozoan infections are associated with IBS development. We systematically searched international databases for all studies that reported these protozoa in IBS patients published by May 10, 2021. Studies were included in the review if they were observational studies with confirmed patients with IBS (in case-control and cross-sectional studies) or parasitic infections (cohort studies) with an appropriate control group. Pooled odds ratios (ORs) and 95% confidence intervals were estimated using a random-effects meta-analysis model for included studies. A total of 32 papers (42 datasets), including 29 papers (31 datasets) for Blastocystis sp./IBS and 11 papers (11 datasets) for G. lamblia/IBS met the eligibility criteria. Our results indicated that the individuals with Blastocystis sp. infection were significantly at a higher risk of IBS development (OR, 1.78; 95%CI, 1.29-2.44). Moreover, cohort studies indicated a significant positive association between G. lamblia infection and IBS risk (OR, 5.47; 95%CI, 4.23-7.08); while an increasing but no statistically significant risk was observed in case-control studies (OR, 1.19; 95%CI, 0.75-1.87). Our findings suggested that Blastocystis sp. and G. lamblia infections are associated with the increased risk of developing IBS. Despite these results, further studies are needed to determine the effect of these protozoa on IBS development.

Toxic heavy metal concentrations in multiple sclerosis patients: A systematic review and meta-analysis.

The present meta-analysis was performed to assess the association between MS patients and control subjects in terms of their circulating levels of arsenic (As), lead (Pb), mercury (Hg), and cadmium (Cd). We searched Medline/PubMed, Scopus, Web of Science, and Embase up until June 2020 to identify all studies that examined the concentrations of heavy metals in MS patients. Statistical tests used to assess inter-study heterogeneity were Cochrane's Q test and the I2 statistic. Given the observed significant heterogeneity, the random-effects model was employed to pool the weighted mean differences (WMDs) and the corresponding 95 % confidence intervals (CIs). Out of a total of 1181 articles, 16 studies with 1650 participants (772 patients with MS and 878 controls) were included in this review meta-analysis. Pooled results using random-effects model showed that the levels of Pb (WMD= 0.73 µg/L, 95 % CI= 0.33 to 1.12, P< 0.001), As (WMD= 2.48 µg/L, 95 % CI= 1.44 to 3.53, P <0.001; I2= 98.9 %, P <0.001), and Cd (WMD= 0.17 µg/L, 95 % CI= 0.09 to 0.26, P <0.001) were significantly higher in MS patients than those of the controls. However, there were no significant differences in the levels of Hg (WMD= -0.14 µg/L, 95 % CI= -0.77 to 0.49, P= 0.658) among both groups. Sensitivity analysis indicated that after excluding one-by-one study, the overall pooled WMD of Pb was changed. This meta-analysis showed that patients with MS had significantly higher levels of circulatory As and Cd compared to the controls. Yet, there was no statistically significant difference between circulating levels of Hg and Pb among MS patients and controls. See also Figure 1(Fig. 1).