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Neuroimaging and Neurodevelopmental Outcome in Extremely Preterm Infants

White matter abnormality (WMA) on neuroimaging is considered a crucial link with adverse neurodevelopmental outcome in preterm infants. Brain MRI is more sensitive in detecting WMA than cranial ultrasound (CUS), but questions remain about timing and prognostic value of modalities.

Near-term CUS and MRI abnormalities were associated with adverse 18- to 22-month outcomes, independent of early CUS and other factors, underscoring the relative prognostic value of later neuroimaging in this large, extremely preterm cohort surviving to near-term. (Read the full article)




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Mental Health of Extremely Low Birth Weight Survivors in Their 30s

Little is known about the mental health of extremely low birth weight survivors in their 30s. It is also unclear whether being born small for gestational age or being exposed to antenatal corticosteroids increases risk in this group.

In their 30s, extremely low birth weight survivors are less likely to have substance problems but are at elevated risk for other psychiatric disorders. Those born small for gestational age are at higher risk, but those exposed to antenatal corticosteroids are at the greatest risk of all. (Read the full article)




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Gestational Age and Developmental Risk in Moderately and Late Preterm and Early Term Infants

There is growing evidence reporting that moderately preterm, late preterm, and early term infants are at increased risk of developmental delay. The characteristics of this association are not well established in the literature.

In a sample of infants born between 32 and 41 weeks, there was an inverse and "dose response" relationship between gestational age and developmental delay risk using the ASQ at 8 and 18 months of corrected postnatal age. (Read the full article)




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Comorbidity of Physical and Mental Disorders in the Neurodevelopmental Genomics Cohort Study

Although there is evidence regarding comorbidity of physical and mental disorders from clinical samples of specific disorders and treatment registries, there is limited evidence from systematic samples of youth with comprehensive information on the full range of mental and physical disorders.

This report is the first study to investigate the specificity of associations between a broad range of mental and physical conditions by using a large, systematically obtained pediatric sample with enriched information from electronic medical records and direct interviews. (Read the full article)




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Neurodevelopmental Outcomes After Cardiac Surgery in Infancy

Neurodevelopmental disabilities are the most common, and potentially the most damaging, sequelae of congenital heart defects. Children with congenital heart defects undergoing surgery in infancy have problems with reasoning, learning, executive function, inattention and impulsive behavior, language skills, and social skills.

Early neurodevelopmental outcomes for survivors of cardiac surgery in infancy have improved modestly over time, but only after adjustment for innate patient risk factors. As more high-risk infants with congenital heart defects survive cardiac surgery, a growing population will require significant societal resources. (Read the full article)




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Developmental Outcomes of Extremely Preterm Infants Born to Adolescent Mothers

Infants born extremely premature and infants born to adolescent mothers are at risk for adverse developmental and behavior outcomes. There is limited research on the dual risk imparted to infants born extremely premature to adolescent mothers.

Extremely premature infants of adolescent mothers have significantly increased rates of behavior problems. Nonwhite race and living in ≥3 places by 18 to 22 months of age are risk factors for adverse behavior outcomes among infants of adolescent mothers. (Read the full article)




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Identifying Priorities for Mental Health Interventions in War-Affected Youth: A Longitudinal Study

War-affected youth often suffer from multiple co-occurring mental health problems. The relationship of these conditions to later mental health has yet to be thoroughly investigated. There is a need to explore potential targets for mental health interventions.

After controlling for preexisting conditions and contemporary confounders, internalizing (depression and anxiety) remained the major predictor of future mental health symptoms (internalizing symptoms, prosocial attitudes/behaviors, and posttraumatic stress symptoms). Interventions targeting internalizing in war-affected youth hold promise. (Read the full article)




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Positive Parenting Practices, Health Disparities, and Developmental Progress

Interactive activities and routines promote early childhood language skills and subsequent educational achievement. Population studies describing parent-child participation in interactive activities and their associations with early child development among vulnerable populations are needed.

Significant disparities exist in parenting practices that promote child development between economically advantaged and disadvantaged parents. Participating in less interactive activities was associated with increased risk of developmental delay among low-income families, suggesting a need to enrich parenting practices. (Read the full article)




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Late Preterm Infants and Neurodevelopmental Outcomes at Kindergarten

Late preterm infants, compared with full-term infants, have less proficiency in reading and math at school age, with increased need for individualized educational plans and special education services. They also have lower cognitive performance on standardized IQ exams.

Late preterm infants have worse outcomes at school entry, and development is variable during the preschool years, so socioeconomic status, language spoken in the home, maternal education, maternal race, and being a late preterm infant have a large impact. (Read the full article)




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Developmental Trajectories of Subjective Social Status

Subjective social status (SSS), a person’s sense of their or their family’s position in the socioeconomic hierarchy, is strongly related to adult health but is not a robust predictor of adolescent health. Developmental trajectories of SSS underlying this discrepancy are unknown.

Five SSS trajectories are present in adolescence/emerging adulthood. Four stably reflect objective socioeconomic status. The fifth represents a subset of socially disadvantaged youth with "rose-colored glasses" early on. Lower SSS and membership in the fifth trajectory increase health risk. (Read the full article)




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Childhood Health and Developmental Outcomes After Cesarean Birth in an Australian Cohort

A number of studies have reported an association between birth by cesarean delivery and adverse childhood health outcomes such as obesity, asthma, atopy, and a number of neurodevelopmental abnormalities. However, these studies have had limited capacity to control for confounders.

Using a prospective cohort while controlling for birth factors, social vulnerability, maternal BMI, and breastfeeding, we found few differences between children delivered by cesarean delivery and those born vaginally. Higher child BMI was explained by maternal BMI. (Read the full article)




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Outpatient Visits and Medication Prescribing for US Children With Mental Health Conditions

Seven percent of children in the United States receive mental health services each year. There are more pediatric outpatient mental health care visits to primary care physicians (PCPs) than to psychiatrists. Mental health utilization patterns regarding different conditions and medication prescribing are unknown.

One-third of children with mental health conditions see PCPs only. A greater proportion of children with attention-deficit/hyperactivity disorder see PCPs for this than do those with anxiety/mood disorders. Children seeing PCPs are prescribed psychotropic medications more often than those seeing psychiatrists. (Read the full article)




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Energy, environmental strategic planning community forums announced for May

The Institutes of Energy and the Environment, in collaboration with Stewarding Our Planet's Resources, announced two separate community forums aimed at providing reports on existing energy and environmental activities and strategic opportunities as well as soliciting community input and recommendations for the future.




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In Vitro and In Vivo Characterization of Potent Antileishmanial Methionine Aminopeptidase-1 Inhibitors [Experimental Therapeutics]

Leishmania major is the causative agent of cutaneous leishmaniasis (CL). No human vaccine is available for CL and current drug regimens present several drawbacks such as emerging resistance, severe toxicity, medium effectiveness, and/or high cost. Thus, the need for better treatment options against CL is a priority. In the present study, we validate the enzyme methionine aminopeptidase-1 (MetAP1), a metalloprotease that catalyzes the removal of N-terminal methionine from peptides and proteins, as a chemotherapeutic target against CL infection. The in vitro antileishmanial activity of eight novel MetAP1 inhibitors (OJT001-OJT008) were investigated. Three compounds OJT006, OJT007, and OJT008 demonstrated potent anti-proliferative effect in macrophages infected with L. major amastigotes and promastigotes at submicromolar concentrations, with no cytotoxicity against host cells. Importantly, the leishmanicidal effect was diminished by almost 10-fold in transgenic L. major promastigotes overexpressing MetAP1LM in comparison to wild-type promastigotes. Furthermore, the in vivo activity of OJT006, OJT007, and OJT008 were investigated in L. major-infected BALB/c mice. In comparison to the control group, OJT008 significantly decreased footpad parasite load by 86%, and exhibited no toxicity against in treated mice. We propose MetAP1 inhibitor OJT008 as a potential chemotherapeutic candidate against CL infection caused by L. major infection.




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ZN148 - a modular synthetic metallo-{beta}-lactamase inhibitor reverses carbapenem-resistance in Gram-negative pathogens in vivo [Experimental Therapeutics]

Carbapenem-resistant Gram-negative pathogens are a critical public health threat and there is an urgent need for new treatments. Carbapenemases (β-lactamases able to inactivate carbapenems) have been identified in both serine β-lactamase (SBL) and metallo β-lactamase (MBL) families. The recent introduction of SBL carbapenemase-inhibitors has provided alternative therapeutic options. Unfortunately, there are no approved inhibitors of MBL-mediated carbapenem-resistance and treatment options for infections caused by MBL-producing Gram-negatives are limited. Here, we present ZN148, a zinc-chelating MBL-inhibitor capable of restoring the bactericidal effect of meropenem and in vitro clinical susceptibility to carbapenems in >98% of a large international collection of MBL-producing clinical Enterobacterales strains (n=234). Moreover, ZN148 was able to potentiate the effect of meropenem against NDM-1-producing Klebsiella pneumoniae in a murine neutropenic peritonitis model. ZN148 showed no inhibition of the human zinc-containing enzyme glyoxylase II at 500 μM and no acute toxicity was observed in an in vivo mouse model with cumulative dosages up to 128 mg/kg. Biochemical analysis showed a time-dependent inhibition of MBLs by ZN148 and removal of zinc ions from the active site. Addition of exogenous zinc after ZN148 exposure only restored MBL activity by ~30%, suggesting an irreversible mechanism of inhibition. Mass-spectrometry and molecular modelling indicated potential oxidation of the active site Cys221 residue. Overall, these results demonstrate the therapeutic potential of a ZN148-carbapenem combination against MBL-producing Gram-negative pathogens and that ZN148 is a highly promising MBL inhibitor, capable of operating in a functional space not presently filled by any clinically approved compound.




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Combination Therapy with Ibrexafungerp (formerly SCY-078), a First-in-Class Triterpenoid Inhibitor of (1->3)-{beta}-D-Glucan Synthesis, and Isavuconazole for Treatment of Experimental Invasive Pulmonary Aspergillosis [Experimental Therapeutics]

Ibrexafungerp (formerly SCY-078) is a semisynthetic triterpenoid and potent (1->3)-β-D-glucan synthase inhibitor. We investigated the in vitro activity, pharmacokinetics, and in vivo efficacy of ibrexafungerp (SCY) alone and in combination with anti-mould triazole isavuconazole (ISA) against invasive pulmonary aspergillosis (IPA). The combination of ibrexafungerp and isavuconazole in in vitro studies resulted in an additive and synergistic interactions against Aspergillus spp. Plasma concentration-time curves of ibrexafungerp were compatible with linear dose proportional profile. In vivo efficacy was studied in a well established persistently neutropenic NZW rabbit model of experimental IPA. Treatment groups included untreated rabbits (UC) and rabbits receiving ibrexafungerp at 2.5(SCY2.5) and 7.5(SCY7.5) mg/kg/day, isavuconazole at 40(ISA40) mg/kg/day, or combinations of SCY2.5+ISA40 and SCY7.5+ISA40. The combination of SCY+ISA produced in vitro synergistic interaction. There was significant in vivo reduction of residual fungal burden, lung weights, and pulmonary infarct scores in SCY2.5+ISA40, SCY7.5+ISA40, and ISA40-treatment groups vs that of SCY2.5-treated, SCY7.5-treated and UC (p<0.01). Rabbits treated with SCY2.5+ISA40 and SCY7.5+ISA40 had prolonged survival in comparison to that of SCY2.5-, SCY7.5-, ISA40-treated or UC (p<0.05). Serum GMI and (1->3)-β-D-glucan levels significantly declined in animals treated with the combination of SCY7.5+ISA40 in comparison to those treated with SCY7.5 or ISA40 (p<0.05). Ibrexafungerp and isavuconazole combination demonstrated prolonged survival, decreased pulmonary injury, reduced residual fungal burden, lower GMI and (1->3)-β-D-glucan levels in comparison to those of single therapy for treatment of IPA. These findings provide an experimental foundation for clinical evaluation of the combination of ibrexafungerp and an anti-mould triazole for treatment of IPA.




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Fosmanogepix (APX001) is Effective in the Treatment of Pulmonary Murine Mucormycosis Due to Rhizopus arrhizus [Experimental Therapeutics]

Mucormycosis is a life-threatening infection with high mortality that occurs predominantly in immunocompromised patients. Manogepix (MGX) is a novel antifungal that targets Gwt1, an early step in the conserved glycosylphosphotidyl inositol (GPI) post-translational modification pathway of surface proteins in eukaryotic cells. Inhibition of inositol acylation by MGX results in pleiotropic effects including inhibition of maturation of GPI-anchored proteins necessary for growth and virulence. MGX has been previously shown to have in vitro activity against some strains of Mucorales. Here we assessed the in vivo activity of the prodrug fosmanogepix, currently in clinical development for the treatment of invasive fungal infections, against two Rhizopus arrhizus strains with high (4.0 μg/ml) and low (0.25 μg/ml) minimum effective concentration (MEC) values. In both invasive pulmonary infection models, treatment of mice with 78 mg/kg or 104 mg/kg fosmanogepix, along with 1-aminobenzotriazole to enhance the serum half-live of MGX in mice, significantly increased median survival time and prolonged overall survival by day 21 post infection when compared to placebo. In addition, administration of fosmanogepix resulted in a 1-2 log reduction in both lung and kidney fungal burden. For the 104 mg/kg fosmanogepix dose, tissue clearance and survival were comparable to clinically relevant doses of isavuconazole (ISA), which is FDA approved for the treatment of mucormycosis. These results support continued development of fosmanogepix as a first in class treatment for invasive mucormycosis.




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Efficacy of bedaquiline, alone or in combination with imipenem, against Mycobacterium abscessus in C3HeB/FeJ mice [Experimental Therapeutics]

Mycobacterium abscessus lung infections remain difficult to treat. Recent studies have recognized the power of new combinations of antibiotics such as bedaquiline and imipenem although in vitro data have questioned this combination. We report that the efficacy of the bedaquiline plus imipenem treatment relies essentially on the activity of bedaquiline in a C3HeB/FeJ mice model of infection with a rough variant of M. abscessus. The addition of imipenem contributed at clearing the infection in the spleen.




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Fenbendazole controls in vitro growth, virulence potential and animal infection in the Cryptococcus model [Experimental Therapeutics]

The human diseases caused by the fungal pathogens Cryptococcus neoformans and C. gattii are associated with high indices of mortality, and toxic and/or cost-prohibitive therapeutic protocols. The need for affordable antifungals to combat cryptococcal disease is unquestionable. Previous studies suggested benzimidazoles as promising anti-cryptococcal agents combining low cost and high antifungal efficacy, but their therapeutic potential has not been demonstrated so far. In this study, we investigated the antifungal potential of fenbendazole, the most effective anti-cryptococcal benzimidazole. Fenbendazole was inhibitory against 17 different isolates of C. neoformans and C. gattii at a low concentration. The mechanism of anti-cryptococcal activity of fenbendazole involved microtubule disorganization, as previously described for human parasites. In combination with fenbendazole, the concentrations of the standard antifungal amphotericin B required to control cryptococcal growth were lower than those required when this antifungal was used alone. Fenbendazole was not toxic to mammalian cells. During macrophage infection, the anti-cryptococcal effects of fenbendazole included inhibition of intracellular proliferation rates and reduced phagocytic escape through vomocytosis. Fenbendazole deeply affected the cryptococcal capsule. In a mice model of cryptococcosis, the efficacy of fenbendazole to control animal mortality was similar to that observed for amphotericin B. These results indicate that fenbendazole is a promising candidate for the future development of an efficient and affordable therapeutic tool to combat cryptococcosis.




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Repurposing the antiamoebic drug diiodohydroxyquinoline for treatment of Clostridioides difficile infections [Experimental Therapeutics]

Clostridioides difficile, the leading cause of nosocomial infections, is an urgent health threat worldwide. The increased incidence and severity of disease, the high recurrence rates, and the dearth of effective anticlostridial drugs have created an urgent need for new therapeutic agents. In an effort to discover new drugs for treatment of Clostridioides difficile infections (CDIs), we investigated a panel of FDA-approved antiparasitic drugs against C. difficile and identified diiodohydroxyquinoline (DIHQ), an FDA-approved oral antiamoebic drug. DIHQ exhibited potent activity against 39 C. difficile isolates, inhibiting growth of 50% and 90% of these isolates at the concentrations of 0.5 μg/mL and 2 μg/mL, respectively. In a time-kill assay, DIHQ was superior to vancomycin and metronidazole, reducing a high bacterial inoculum by 3-log10 within six hours. Furthermore, DIHQ reacted synergistically with vancomycin and metronidazole against C. difficile in vitro. Moreover, at subinhibitory concentrations, DIHQ was superior to vancomycin and metronidazole in inhibiting two key virulence factors of C. difficile, toxin production and spore formation. Additionally, DIHQ did not inhibit growth of key species that compose the host intestinal microbiota, such as Bacteroides, Bifidobacterium and Lactobacillus spp. Collectively, our results indicate that DIHQ is a promising anticlostridial drug that warrants further investigation as a new therapeutic for CDIs.




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Development of probiotic formulations for oral candidiasis prevention: Gellan gum as a carrier to deliver Lactobacillus paracasei 28.4 [Experimental Therapeutics]

Probiotics might provide an alternative approach for the control of oral candidiasis. However, studies on the antifungal activity of probiotics in the oral cavity are based on the consumption of yogurt or other dietary products, and there is a necessary to use appropriate biomaterials and specific strains to obtain probiotic formulations targeting local oral administration. In this study, we impregnated gellan gum, a natural biopolymer used as a food-additive, with a probiotic and investigated its antifungal activity against Candida albicans. Lactobacillus paracasei 28.4, a strain recently isolated from the oral cavity of a caries-free individual, was incorporated in several concentrations of gellan gum (0.6% to 1%). All tested concentrations could incorporate L. paracasei cells while maintaining bacterial viability. Probiotic/gellan formulations were stable for 7 days when stored at room temperature or 4°C. Long-term storage of bacteria-impregnated gellan gum was achieved when L. paracasei 28.4 was lyophilized. The probiotic/gellan formulations provided a release of L. paracasei cells over 24 hours that was sufficient to inhibit the growth of C. albicans with effects dependent on the cell concentrations incorporated into gellan gum. The probiotic/gellan formulations also had inhibitory activity against Candida spp. biofilms by reducing the number of Candida spp. cells (p < 0.0001), decreasing the total biomass (p = 0.0003), and impairing hyphae formation (p = 0.0002), compared to the control group which received no treatment. Interestingly, probiotic formulation of 1% w/v gellan gum provided an oral colonization of L. paracasei in mice with approximately 6 log of CFU/mL after 10 days. This formulation inhibited the C. albicans growth (p < 0.0001), prevented the development of candidiasis lesions (p = 0.0013), and suppressed inflammation (p = 0.0006) when compared to the mice not treated in the microscopic analysis of the tongue dorsum. These results indicate that gellan gum is a promising biomaterial and can be used as a carrier system to promote oral colonization for probiotics that prevent oral candidiasis.




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The Added Value of Longitudinal Imaging for Preclinical In vivo Efficacy Testing of Therapeutic Compounds against Cerebral Cryptococcosis [Experimental Therapeutics]

Brain infections with Cryptococcus neoformans are associated with significant morbidity and mortality. Cryptococcosis typically presents as meningoencephalitis or fungal mass lesions called cryptococcomas. Despite frequent in vitro discoveries of promising novel antifungals, the clinical need for drugs that can more efficiently treat these brain infections remains. A crucial step in drug development is the evaluation of in vivo drug efficacy in animal models. This mainly relies on survival studies or post-mortem analyses in large groups of animals, but these techniques only provide information on specific organs of interest at predefined time points. In this proof-of-concept study, we validated the use of non-invasive preclinical imaging to obtain longitudinal information on the therapeutic efficacy of amphotericin B or fluconazole monotherapy in meningoencephalitis and cryptococcoma mouse models. Bioluminescence imaging (BLI) enabled the rapid in vitro and in vivo evaluation of drug efficacy while complementary high-resolution anatomical information obtained by magnetic resonance imaging (MRI) of the brain allowed a precise assessment of the extent of infection and lesion growth rates. We demonstrated a good correlation between both imaging readouts and the fungal burden in various organs. Moreover, we identified potential pitfalls associated with the interpretation of therapeutic efficacy based solely on post-mortem studies, demonstrating the added value of this non-invasive dual imaging approach compared to standard mortality curves or fungal load endpoints. This novel preclinical imaging platform provides insights in the dynamic aspects of the therapeutic response and facilitates a more efficient and accurate translation of promising antifungal compounds from bench to bedside.




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Therapeutic efficacy of a mixed formulation of conventional and PEGylated liposomes containing meglumine antimoniate, combined with allopurinol, in dogs naturally infected with Leishmania infantum [Experimental Therapeutics]

Treatment of dogs naturally infected with Leishmania infantum using meglumine antimoniate (MA) encapsulated in conventional liposomes (LC) in association with allopurinol has been previously reported to promote marked reduction in the parasite burden in the main infection sites. Here, a new assay in naturally infected dogs was performed using a novel liposome formulation of MA consisting of a mixture of conventional and long-circulating (PEGylated) liposomes (LCP), with expected broader distribution among affected tissues of the mononuclear phagocyte system. Experimental groups of naturally infected dogs were as follows: LCP+Allop, receiving LCP intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose) at 4-day intervals, plus allopurinol at 30 mg/kg/12 h p.o. during 130 days; LC+Allop, receiving LC intravenously as 2 cycles of 6 doses (6.5 mg Sb/kg/dose), plus allopurinol during 130 days; Allop, treated with allopurinol only; non-treated control. Parasite loads were evaluated by quantitative PCR in liver, spleen and bone marrow and by immunohistochemistry in the ear skin, before, just after treatment and 4 months later. LCP+Allop and LC+Allop groups, but not the Allop group, showed significant suppression of the parasites in the liver, spleen and bone marrow 4 months after treatment, compared to the pre-treatment period or the control group. Only LCP+Allop group showed significantly lower parasite burden in the skin, in comparison to the control group. On the basis of clinical staging and parasitological evaluations, LCP formulation exhibited a more favorable therapeutic profile, when compared to LC one, being therefore promising for treatment of canine visceral leishmaniasis.




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Experimentally engineered mutations in a ubiquitin hydrolase, UBP-1, modulate in vivo susceptibility to artemisinin and chloroquine in Plasmodium berghei. [Mechanisms of Resistance]

As resistance to artemisinins (current frontline drugs in malaria treatment) emerges in south East Asia, there is an urgent need to identify the genetic determinants and understand the molecular mechanisms underpinning such resistance. Such insights could lead to prospective interventions to contain resistance and prevent the eventual spread to other malaria endemic regions. Artemisinin reduced susceptibility in South East Asia (SEA) has been primarily linked to mutations in P. falciparum Kelch-13, which is currently widely recognised as a molecular marker of artemisinin resistance. However, 2 mutations in a ubiquitin hydrolase, UBP-1, have been previously associated with artemisinin reduced susceptibility in a rodent model of malaria and some cases of UBP-1 mutation variants associating with artemisinin treatment failure have been reported in Africa and SEA. In this study, we have employed CRISPR-Cas9 genome editing and pre-emptive drug pressures to test these artemisinin susceptibility associated mutations in UBP-1 in P. berghei sensitive lines in vivo. Using these approaches, we have shown that the V2721F UBP-1 mutation results in reduced artemisinin susceptibility, while the V2752F mutation results in resistance to chloroquine and moderately impacts tolerance to artemisinins. Genetic reversal of the V2752F mutation restored chloroquine sensitivity in these mutant lines while simultaneous introduction of both mutations could not be achieved and appears to be lethal. Interestingly, these mutations carry a detrimental growth defect, which would possibly explain their lack of expansion in natural infection settings. Our work has provided independent experimental evidence on the role of UBP-1 in modulating parasite responses to artemisinin and chloroquine under in vivo conditions.




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Combination Therapy Using Benznidazole and Aspirin During the Acute Phase of Experimental Chagas Disease Prevents Cardiovascular Dysfunction and Decreases Typical Cardiac Lesions in the Chronic Phase [Clinical Therapeutics]

Chagas disease, caused by the protozoan Trypanosoma cruzi, is one of the main causes of death due to cardiomyopathy and heart failure in Latin American countries. The treatment of Chagas disease is directed at eliminating the parasite, decreasing the probability of cardiomyopathy, and disrupting the disease transmission cycle. Benznidazole (BZ) and nifurtimox (NFX) are recognized as effective drugs for the treatment of Chagas disease by the World Health Organization, but both have high toxicity and limited efficacy, especially in the chronic disease phase. At low doses, aspirin (ASA) has been reported to protect against T. cruzi infection. We evaluated the effectiveness of BZ in combination with ASA at low doses during the acute disease phase and evaluated cardiovascular aspects and cardiac lesions in the chronic phase. ASA treatment prevented the cardiovascular dysfunction (hypertension and tachycardia) and typical cardiac lesions. Moreover, BZ+ASA-treated mice had a smaller cardiac fibrotic area than that in BZ-treated mice. These results were associated with an increase in the number of eosinophils and reticulocytes and level of nitric oxide in the plasma and cardiac tissue of ASA-treated mice relative to respective controls. These effects of ASA and BZ+ASA in chronically infected mice were inhibited by pretreatment with the LXA4 receptor antagonist, Boc-2, indicating that the protective effects of ASA are mediated by ASA-triggered lipoxin. These results emphasize the importance of exploring new drug combinations for treatments of acute phase of Chagas disease that are beneficial for chronic patients.




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Body Dissatisfaction and Mental Health Outcomes of Youth on Gender-Affirming Hormone Therapy

OBJECTIVES:

Our first aim was to examine baseline differences in body dissatisfaction, depression, and anxiety symptoms by gender, age, and Tanner (ie, pubertal) stage. Our second aim was to test for changes in youth symptoms over the first year of receiving gender-affirming hormone therapy. Our third aim was to examine potential differences in change over time by demographic and treatment characteristics. Youth experiences of suicidal ideation, suicide attempt, and nonsuicidal self-injury (NSSI) are also reported.

METHODS:

Participants (n = 148; ages 9–18 years; mean age 14.9 years) were receiving gender-affirming hormone therapy at a multidisciplinary program in Dallas, Texas (n = 25 puberty suppression only; n = 123 feminizing or masculinizing hormone therapy). Participants completed surveys assessing body dissatisfaction (Body Image Scale), depression (Quick Inventory of Depressive Symptoms), and anxiety (Screen for Child Anxiety Related Emotional Disorders) at initial presentation to the clinic and at follow-up. Clinicians completed the Quick Inventory of Depressive Symptoms and collected information on youth experiences of suicidal ideation, suicide attempt, and NSSI.

RESULTS:

Affirmed males reported greater depression and anxiety at baseline, but these differences were small (P < .01). Youth reported large improvements in body dissatisfaction (P < .001), small to moderate improvements in self-report of depressive symptoms (P < .001), and small improvements in total anxiety symptoms (P < .01). No demographic or treatment-related characteristics were associated with change over time. Lifetime and follow-up rates were 81% and 39% for suicidal ideation, 16% and 4% for suicide attempt, and 52% and 18% for NSSI, respectively.

CONCLUSIONS:

Results provide further evidence of the critical role of gender-affirming hormone therapy in reducing body dissatisfaction. Modest initial improvements in mental health were also evident.




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Mental Health Outcomes Among Homeless, Runaway, and Stably Housed Youth

BACKGROUND AND OBJECTIVES:

Runaway youth and homeless youth are at risk for adverse mental health outcomes. These 2 populations are frequently pooled together in both research and interventions yet may have unique health needs. We sought to assess differences in mental health outcomes among these populations.

METHODS:

We conducted a secondary data analysis of ninth- and 11th-graders in the 2016 minnesota Student Survey (n = 68 785). We categorized youth into 4 subgroups based on housing status in the previous year: (1) unaccompanied homeless youth (0.5%), (2) runaway youth (4%), (3) youth who had both run away and been homeless (0.6%), and (4) stably housed youth (95%). We performed multivariable logistic regression to compare 4 mental health outcomes (self-injury, suicidal ideation, suicide attempts, and depressive symptoms) across groups, controlling for demographics and abuse history.

RESULTS:

Unstably housed youth had poorer mental health outcomes when compared with their stably housed peers (P < .05). For example, 11% of homeless youth, 20% of runaways, and 33% of youth who had experienced both had attempted suicide in the previous year compared with 2% of stably housed youth (adjusted odds ratios 2.4, 4.9, and 7.1, respectively). Other outcomes showed a similar pattern.

CONCLUSIONS:

Our findings suggest that runaway and homeless youth represent unique populations with high levels of mental health needs who would benefit from targeted clinical and community interventions. Pediatric clinicians represent one potential point of screening and intervention.




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Trends in Pediatricians Developmental Screening: 2002-2016

BACKGROUND:

Current guidelines from the American Academy of Pediatrics recommend screening children for developmental problems by using a standardized screening tool and referring at-risk patients to early intervention (EI) or subspecialists. Adoption of guidelines has been gradual, with research showing many children still not being screened and referred.

METHODS:

We analyzed American Academy of Pediatrics Periodic Survey data from 2002 (response rate = 58%; N = 562), 2009 (response rate = 57%; N = 532), and 2016 (response rate = 47%, N = 469). Surveys included items on pediatricians’ knowledge, attitudes, and practices regarding screening and referring children for developmental problems. We used descriptive statistics and a multivariable logistic regression model to examine trends in screening and referral practices and attitudes.

RESULTS:

Pediatricians’ reported use of developmental screening tools increased from 21% in 2002 to 63% in 2016 (P < .001). In 2016, on average pediatricians reported referring 59% of their at-risk patients to EI, up from 41% in 2002 (P < .001), and pediatricians in 2016 were more likely than in 2002 to report being "very likely" to refer a patient with global developmental delay, milestone loss, language delay, sensory impairment, motor delays, and family concern to EI.

CONCLUSIONS:

Pediatricians’ reported use of a standardized developmental screening tool has tripled from 2002 to 2016, and more pediatricians are self-reporting making referrals for children with concerns in developmental screening. To sustain this progress, additional efforts are needed to enhance referral systems, improve EI programs, and provide better tracking of child outcomes.




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Mental Health of Transgender Children Who Are Supported in Their Identities

Kristina R. Olson
Mar 1, 2016; 137:e20153223-e20153223
ARTICLES




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World Campus helps students find mental health services no matter where they are

Katie Marshall, Penn State World Campus mental health case manager, connects students learning online to resources in their own communities.




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Neurodevelopmental Outcomes of Preterm Infants With Retinopathy of Prematurity by Treatment




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ADHD, Other Developmental Disabilities More Common in Rural Areas

Rural families are less likely to use special education or early intervention services than children living in urban areas, a new Centers for Disease Control survey reveals.




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Trends in the Prevalence of Developmental Disabilities in US Children, 1997-2008

Coleen A. Boyle
Jun 1, 2011; 127:1034-1042
ARTICLES




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Supplemental Therapeutic Oxygen for Prethreshold Retinopathy of Prematurity (STOP-ROP), A Randomized, Controlled Trial. I: Primary Outcomes

The STOP-ROP Multicenter Study Group
Feb 1, 2000; 105:295-310
ARTICLES




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Growth in the Neonatal Intensive Care Unit Influences Neurodevelopmental and Growth Outcomes of Extremely Low Birth Weight Infants

Richard A. Ehrenkranz
Apr 1, 2006; 117:1253-1261
ARTICLES




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Neurodevelopmental and Functional Outcomes of Extremely Low Birth Weight Infants in the National Institute of Child Health and Human Development Neonatal Research Network, 1993-1994

Betty R. Vohr
Jun 1, 2000; 105:1216-1226
ARTICLES




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The Path to Fluent Reading: A Developmental Timeline

Some of the most important pre-literacy skills begin in infancy. This timeline shows examples of the milestones children meet on their path to fluent reading.




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Sacramental confession and the certainty of forgiveness

By Bishop Arthur Serratelli

A few years ago, Paul Croituru and his young son went out treasure hunting near their native village in Romania. To their surprise, they discovered ancient Greek currency dating back 2,350 years to the time of King Philip II. The 300 silver coins turned out to be counterfeit. The father and son now hold the distinction of having discovered the oldest counterfeit money known thus far.

Counterfeit money has been around as long as money has been around. In fact, some have named the production of counterfeit money “the world's second oldest profession.” During war time, nations often resort to counterfeit money to inflict harm on their enemies. During the Revolutionary War, Great Britain attempted to devalue the continental dollar by flooding the market with shovers (fake dollars). During World War II, the Nazis made prisoners in their camps forge British pounds and American dollars to destabilize their enemies’ economies and destroy them.

Satan constantly attempts to entice individuals into counterfeit religion where the forged currency is believing in God while denying sin. The devil would have everyone forget that sin is a reality. In this way, he can render ineffective in us the work of Christ who came to take away our sins. Failure. Weakness. Mistakes. Psychological pressures. Social customs. All these labels the devil uses to disguise sin. But, sin itself remains a fact.

Science always prides itself on beginning every research project with a fact. True religion, likewise, begins with the fact of sin in the world, original sin and personal sin. “The ancient masters of religion…began with the fact of sin. Whether or not man could be washed in miraculous waters, there was no doubt at any rate that he wanted washing. But certain religious leaders…have begun…to deny the indisputable dirt. Certain new theologians dispute original sin, which is the only part of Christian theology which can really be proved” (G.K. Chesterton, Orthodoxy). And so can the personal sins of hatred, envy, lust, pride, gluttony and greed likewise be proven.

Even a casual glance at Sacred Scriptures shows that sin taints even God’s greatest heroes and heroines. Adam and Eve lead the procession of sinners. Drunken Noah, untruthful Abraham, adulterous David and Bathsheba, disloyal Peter, and murderous Paul follow. Sin really is not that original. It is the monotonous repetition of the tragedy of Eden: choosing self over God. “If we say that we have no sin, we deceive ourselves, and the truth is not in us” (1 Jn 1:8).

In the Sacrament of Penance, the Church offers us the gift of a personal encounter with our merciful Lord who forgives our sins. However, many people, and sometimes even faithful Catholics, say that they do not need to go to a priest for confession to have their sins forgiven. Why confess to a priest who is a sinner himself? God will forgive sins without the ministry of priests. Certainly, God can forgive sins when we turn to him and repent. But, he has chosen to offer us his forgiveness through the ministry of the Church. And, for a reason.

Sin is not just between the individual and God. Every sin that we commit offends God and affects others. Every sin harms Christ’s Body, the Church. The act of confession before a priest recognizes the true nature of sin as an offense against God and others. And so, it is through the Church’s priests that God chooses not simply to forgive our sins but to reconcile us to the Church. (cf. Pope Francis, General Audience, November 20, 2013).

So important is confession that some of the holiest priests of the Church have spent hours in the confessional as missionaries of God’s mercy. St. Philip Neri, a busy parish priest in Rome, spent every morning hearing confessions before continuing his work with youth in the afternoon. So famous was St. Jean Vianney in hearing confessions that a new train station had to be built in his town of Ars so that people from all of France could go there to confess to this holy priest. Most recently, St. Padre Pio heard confessions for not less than 18 hours a day. There were always long lines awaiting him.  

During his public ministry, Jesus forgave sins (cf. Mk 2:5; Lk 7:48; Jn 8:1-11). And, then after the Resurrection, he entrusted this ministry of forgiveness to his priests. On Easter Sunday night, “Jesus said to them ‘Peace be with you. As the Father has sent me, so I send you.’ And when he had said this, he breathed on them and said to them, ‘Receive the Holy Spirit. Whose sins you forgive are forgiven them, and whose sins you retain are retained’” (Jn 20:21-23). In confession, the priest, weak and sinful himself, acts in the name of Jesus and with his authority.  

In going to confession, we approach the priest, one by one, not as group, not as family. We humbly place before him all our own sins. To receive absolution and be forgiven, it is necessary not simply to confess all mortal sins, but also to have a firm purpose of amendment of sinning no more. As difficult as this might be at times, how great the grace! For, when the priest absolves us, we have, as Jesus promised, the certainty that our sins are forgiven. 



  • CNA Columns: From the Bishops

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