Roles of physical functioning and comorbid mental illness of chronically ill parents and their spouses' health status in adolescent functioning.

INTRODUCTION: Emerging research suggests that physically ill parents' psychological adjustment to illness and emotional well-being may affect adolescents' psychosocial functioning. As people with chronic medical conditions often develop mental disorders, it is important to examine the influence of comorbidity of parental physical and mental health conditions on adolescents' functioning. In addition, the physical and mental health status of the spouses/partners of chronically ill parents needs to be explored to further understand the potential impact of parental chronic illness on adolescents' psychological distress and academic performance. METHODS: Cross-sectional data from 164 parent-adolescent pairs were collected through online surveys in the United States between 2018 and 2019. Parent participants (Mage = 42.69, SD = 5.96) included parents who had been diagnosed with a chronic physical illness (e.g., multiple sclerosis, diabetes, chronic pain, cancer). Adolescent participants were middle- and high-school-aged children who lived with their physically ill parents (Mage = 14.34, SD = 2.07). RESULTS: Hierarchical regression analyses indicated that comorbid mental illness of parental chronic illness and spousal mental health status were associated with adolescents' distress. The level of physical functioning of chronically ill parents was related to adolescents' academic performance. CONCLUSION: Parental chronic illness appears to affect adolescents' psychological and academic outcomes through distinct pathways. It is important to examine the comorbid mental health status of chronically ill parents and their spouses'/partners' mental health conditions to better understand the impact of parental chronic illness on adolescents' psychological adjustment.

Long-term outcomes in two adult siblings with Fucosidosis - Diagnostic odyssey and clinical manifestations.

Fucosidosis (OMIN# 230000) is a rare lysosomal storage disorder (LSDs) caused by mutations in the FUCA1 gene, leading to alpha-L-fucosidase deficiency; it is inherited as an autosomal recessive trait. Fucosidosis represents a disease spectrum with a wide variety of clinical features, but most affected patients have slow neurologic deterioration. Many patients die young and the long-term clinical outcomes in adult patients are poorly documented. Here, we report the long-term follow up of two Caucasian siblings, a 31-year-old man and 25-year-old woman. We describe the clinical, biochemical, radiological and genetic findings in two siblings affected by Fucosidosis and the differences between them after 19-years follow up. The dermatological features of the younger sibling have been reported previously by Bharati et al. (2007). Both patients have typical features of Fucosidosis, such as learning difficulties, ataxia, and angiokeratomas with differing severity. Case 1 presents severe ataxia with greater limitation of mobility, multiple dysostoses, angiokeratomas on his limbs, retinal vein enlargement and increased tortuosity in the eye and gastrointestinal symptoms. Biochemical analysis demonstrated a deficiency of alpha-fucosidase in leucocytes. Case 2 has a greater number of angiokeratomas and has suffered three psychotic episodes. The diagnosis of Fucosidosis was confirmed in cultured skin fibroblast at the age of 12 years. Molecular analysis of the FUCA1 gene showed a heterozygous mutation c.998G > A p.(Gly333Asp), with a pathogenic exon 4 deletion in the other allele in both patients. Conclusion. Fucosidosis presents a wide clinical heterogeneity and intrafamilial variability of symptoms. Psychosis and gastrointestinal symptoms have not been reported previously in Fucosidosis.

Spontaneous secondary pneumothorax due to cannabis-induced bullous lung disease: a case report.

Marijuana use has grown rapidly in the last decade with a prevalence greater than that of cocaine and opioids. With its increasing recreational and medical use, potential adverse outcomes from heavy use may be associated with bullous lung disease and spontaneous pneumothorax. This case report has been reported in line with the SCARE Criteria. Case presentation: The authors describe a case of an adult male with a past medical history of spontaneous pneumothorax and long-standing marijuana use presenting with dyspnoea who was found to have a secondary spontaneous pneumothorax requiring invasive treatment. Clinical discussion: The aetiology of lung injury due to heavy marijuana smoke may be from direct tissue injury from inhaled irritants and the method of which marijuana smoke is inhaled compared with tobacco smoke. Conclusion: Chronic marijuana use should be considered when evaluating structural lung disease and pneumothorax in the setting of minimal tobacco use.

A Bayesian predictive processing account of Othello syndrome in Parkinson's disease.

Introduction: Although delusions in Parkinson's disease (PD) are rare, when they occur they frequently take the form of "Othello syndrome": the irrational belief that a spouse or partner is being unfaithful. Hitherto dismissed as either a by-product of dopamine therapy or cognitive impairment, there are still no convincing theoretical accounts to explain why only some patients fall prey to this delusion, or why it persists despite clear disconfirmatory evidence.Methods: We discuss the limitations of existing explanations of this delusion, namely hyperdopaminergia-induced anomalous perceptual experiences and cognitive impairment, before describing how Bayesian predictive processing accounts can provide a more comprehensive explanation by foregrounding the importance of prior experience and its impact upon computation of probability. We illustrate this new conceptualisation with three case vignettes.Results: We suggest that in those with prior experience of romantic betrayal, hyperdominergic-induced aberrant prediction errors enable anomalous perceptual experiences to accrue greater prominence, which is then maintained through Bayes-optimal inferencing to confirm cognitive distortions, eliciting and shaping this dangerous delusion.Conclusions: We propose the first comprehensive mechanistic account of Othello syndrome in PD and discuss implications for clinical interventions.

Biochemical, Genetic and Clinical Diagnostic Approaches to Autism-Associated Inherited Metabolic Disorders.

Autism spectrum disorders (ASD) are a heterogeneous group of neurodevelopmental disorders characterized by impaired social interaction, limited communication skills, and restrictive and repetitive behaviours. The pathophysiology of ASD is multifactorial and includes genetic, epigenetic, and environmental factors, whereas a causal relationship has been described between ASD and inherited metabolic disorders (IMDs). This review describes biochemical, genetic, and clinical approaches to investigating IMDs associated with ASD. The biochemical work-up includes body fluid analysis to confirm general metabolic and/or lysosomal storage diseases, while the advances and applications of genomic testing technology would assist with identifying molecular defects. An IMD is considered likely underlying pathophysiology in ASD patients with suggestive clinical symptoms and multiorgan involvement, of which early recognition and treatment increase their likelihood of achieving optimal care and a better quality of life.

Neuropsychology assessment and outcomes in adult mucopolysaccharidosis - A systematic review as the first step to service development in a large tertiary Lysosomal Storage Disorders centre.

A systematic review of Randomised Controlled Trials in adult mucopolysaccharidoses (MPSs) was conducted to inform neuropsychology service development at a large tertiary Lysosomal Storage Diseases centre. Studies including psychological endpoints for cognition, mood, and quality of life were reviewed. Forty-eight studies met the inclusion criteria for full text review. Of the 48 studies, 44% (21/48) included adult participants, while psychological endpoints were used in 52% (25/48) for cognition, 11% (5/48) for mood, and 69% (33/48) for quality of life. Five studies included both adult participants and relevant psychological endpoints. Risk of bias ratings were 'high' for two studies, while two studies received a rating of 'some concerns', and the last study a 'low' risk of bias rating. The evidence base for psychological outcomes in adult MPS disorders is limited and insufficient for guiding neuropsychology service development. Data on the psychosocial effects of MPS across the lifespan will be crucial for planning service development and supporting the neuropsychological needs of adult patients and their families.

Update on the Cognitive Presentations of iNPH for Clinicians.

This mini-review focuses on cognitive impairment in iNPH. This symptom is one of the characteristic triad of symptoms in a condition long considered to be the only treatable dementia. We present an update on recent developments in clinical, neuropsychological, neuroimaging and biomarker aspects. Significant advances in our understanding have been made, notably regarding biomarkers, but iNPH remains a difficult diagnosis. Stronger evidence for permanent surgical treatment is emerging but selection for treatment remains challenging, particularly with regards to cognitive presentations. Encouragingly, there has been increasing interest in iNPH, but more research is required to better define the underlying pathology and delineate it from overlapping conditions, in order to inform best practise for the clinician managing the cognitively impaired patient. In the meantime, we strongly encourage a multidisciplinary approach and a structured service pathway to maximise patient benefit.

A Preliminary Study of COVID-19-related Stressors, Parenting Stress, and Parental Psychological Well-being Among Parents of School-age Children.

The COVID-19 pandemic has had substantial health, social, and economic effects on families. Consequent lockdowns and school closures heightened the burden on parents of school-age children. Many parents, while working from home, had to care for their children with restricted access to caregiver resources and to support their children's education through homeschooling or remote learning provided by their schools. These duties created challenges and pressures on parents. Using online survey data collected from 197 parents of school-age (Prek-12) children during the first three months of the COVID-19 pandemic in the U.S., this preliminary study examined the relations among COVID-19-related stressors, including fear of COVID-19 and problems associated with school closures, parenting stress, and parental psychological well-being. Fear of COVID-19 and various issues associated with school closures were related to parenting stress and parental well-being. Parents with less instrumental and emotional support reported higher levels of parenting stress and lower levels of psychological well-being. The results of hierarchical multiple regressions revealed that parenting stress was the strongest predictor of parental psychological distress. Social support was associated with parental well-being but did not mediate the relation between parenting stress and parental well-being. The findings suggest that parenting stress during the COVID-19 lockdowns might take a toll on the mental health of parents of school-age children. Parents of school-age children need multiple layers of support, including targeted support addressing stressors related to school closures and parenting under quarantine.

Repression of Organic Anion Transporting Polypeptide (OATP) 1B Expression and Increase of Plasma Coproporphyrin Level as Evidence for OATP1B Downregulation in Cynomolgus Monkeys Treated with Chenodeoxycholic Acid.

Farnesoid X receptor (FXR) is a nuclear receptor known to markedly alter expression of major transporters and enzymes in the liver. However, its effects toward organic anion transporting polypeptides (OATP) 1B1 and 1B3 remain poorly characterized. Therefore, the present study was aimed at determining the effects of chenodeoxycholic acid (CDCA), a naturally occurring FXR agonist, on OATP1B expression in cynomolgus monkeys. Multiple administrations of 50 and 100 mg/kg of CDCA were first shown to significantly repress mRNA expression of SLCO1B1/3 approximately 60% to 80% in monkey livers. It also suppressed cytochrome P450 (CYP)7A1-mRNA and induced OSTα/ß-mRNA, which are well known targets of FXR and determinants of bile acid homeostasis. CDCA concomitantly decreased OATP1B protein abundance by approximately 60% in monkey liver. In contrast, multiple doses of 15 mg/kg rifampin (RIF), a pregnane X receptor agonist, had no effect on hepatic OATP1B protein, although it induced the intestinal P-glycoprotein and MR2 proteins by ∼2-fold. Moreover, multiple doses of CDCA resulted in a steady ∼2- to 10-fold increase of the OATP1B biomarkers coproporphyrins (CPs) in the plasma samples collected prior to each CDCA dose. Additionally, 3.4- to 11.2-fold increases of CPI and CPIII areas under the curve were observed after multiple administrations compared with the single dose and vehicle administration dosing groups. Taken together, these data suggest that CDCA represses the expression of OATP1B1 and OATP1B3 in monkeys. Further investigation of OATP1B downregulation by FXR in humans is warranted, as such downregulation effects may be involved in bile acid homeostasis and potential drug interactions in man. SIGNIFICANCE STATEMENT: Using gene expression and proteomics tools, as well as endogenous biomarker data, for the first time, we have demonstrated that OATP1B expression was suppressed and its activity was reduced in the cynomolgus monkeys following oral administration of 50 and 100 mg/kg/day of chenodeoxycholic acid (CDCA), a Farnesoid X receptor agonist, for 8 days. These results lead to a better understanding of OATP1B downregulation by CDCA and its role on bile acid and drug disposition.

Grieving During the COVID-19 Pandemic: In-Person and Virtual "Goodbye".

This study examined the relationship between having an opportunity to say goodbye to a dying family member or friend in person or virtually, as well as attending their funeral services in person or virtually, and the bereaved individuals' psychological distress and complicated grief during the COVID-19 pandemic. Five hundred and nineteen US adults who had lost a family member or a friend between January 2020 and June 2021 completed an online survey for this study. Only a small proportion of participants were able to say goodbye to their dying family member or friend in person, and saying goodbye virtually was associated with higher levels of complicated grief and psychological distress. Those who physically attended a formal, in-person funeral or memorial service reported lower levels of psychological distress. The findings suggest a complicated process of saying goodbye in different formats during the pandemic.

Non-cardiac Manifestations in Adult Patients With Mucopolysaccharidosis.

Mucopolysaccharidoses (MPS) are a heterogeneous group of disorders that results in the absence or deficiency of lysosomal enzymes, leading to an inappropriate storage of glycosaminoglycans (GAGs) in various tissues of the body such as bones, cartilage, heart valves, arteries, upper airways, cornea, teeth, liver and nervous system. Clinical manifestations can become progressively exacerbated with age and affect their quality of life. Developments in advanced supportive treatment options such as enzyme replacement therapy (ERT), hematopoietic stem cell transplantation (HSCT) may have improved patients' life span. Adult MPS patients require specialist clinical surveillance long-term. In many cases, in addition to the MPS-related health problems, they may develop age-related complications. Considering the complexity of their clinical manifestations and lack of guidelines on the management of adult MPS disorders, multispecialty and multidisciplinary teams' care is essential to diagnose and treat health problems that are likely to be encountered. This review presents non-cardiac clinical manifestations, their pathophysiology, management and long-term outcomes in adult MPS patients.

Acute Salmonella typhimurium Aneurysmal Aortitis With Bacteremia, Pneumonia, and Thoracic Aortic Dissection in an Elderly Male.

Nontyphoidal Salmonellae (NTS) often cause self-limiting gastroenteritis in adults, known as salmonellosis. Salmonellosis has remained controlled in the United States due to intensive measures. Infrequently, these patients develop bacteremia and local or disseminated infections after salmonellosis. NTS endovascular infections are frequent in patients with immunosuppression, indwelling prosthetic vascular grafts, atherosclerotic vascular disease, or aortic aneurysms. NTS endovascular infections are uncommon in immunocompetent adults. Similarly, other focal extraintestinal infections such as pneumonia are also rare. A PubMed review of the medical literature reveals few cases in healthy adults with bacteremia, pneumonia, and acute infectious thoracic aortitis with dissection due to Salmonella typhimurium. We present an elderly White male with salmonellosis followed by S. typhimurium bacteremia with pneumonia and an acute thoracic aortic dissection three weeks later. He was treated successfully with endovascular repair and antibiotics.

Psychosocial factors associated with mask-wearing behavior during the COVID-19 pandemic.

Although increasing evidence has supported the efficacy of masks to prevent the spread of the coronavirus (COVID-19), inconsistent and noncompliant mask-wearing behavior has been observed among members of the society. Because mask-wearing is often considered a social contract, it is important to understand the psychosocial factors that influence people's mask-wearing behavior in order to implement the necessary steps to respond to the pandemic. Based on the protection motivation theory (PMT), this study examined the cognitive factors (threat and coping appraisals) that contribute to mask-wearing behavior and the intention to engage in health protective behavior until the end of the pandemic. Furthermore, we examined the roles of social (perceived social norm) and affective (fear) factors in mask-wearing behavior and intention. The sample included 981 voluntary adults in the United States who completed an online survey for this study between 15 October 2020 and 28 November 2020. The results of hierarchical multiple regressions showed that all PMT variables (severity, susceptibility, response efficacy, and self-efficacy) were associated with mask-wearing behavior and intention to engage in health protective behavior until the end of the pandemic. Perceived social norm and fear provided unique, additive contributions to the predictability of mask-wearing behavior and intention. Overall findings suggest the importance of considering cognitive, social, and affective factors altogether in order to better understand an individual' intention and behavior toward mask wearing during the pandemic.

Impact of the 2020 pandemic of COVID-19 on Families with School-aged Children in the United States: Roles of Income Level and Race.

This study examined the experiences of families with school-aged children during the first three months of the 2020 pandemic of COVID-19 in the United States, while focusing on the roles of income level and race/ethnicity in their experiences. Two hundred and twenty-three parents of school-aged children participated in this study by completing an online survey. The results revealed that low-income and lower-middle class parents, as well as parents of color, experienced more instrumental and financial hardships due to the pandemic, when compared to their higher income, White counterparts. In contrast, parents with higher income and White parents were more likely to feel stressed over structuring home learning environments and planning educational and physical activities at home for their children. The overall findings suggest that family income level and race/ethnicity play a significant role in the lives of families coping with a variety of challenges due to the pandemic.

Individual factors and cisgender college students' attitudes and behaviors toward transgender individuals.

The present study is one of few to investigate both anti-trans discrimination and anti-trans prejudice. It examined four individual factors (religiosity; political beliefs; affiliation with LGBTQ [lesbian, gay, bisexual, transgender, and queer] people; gender role beliefs) through a lens of hetero-cis-normativity to understand their association with anti-trans attitudes and reported behaviors. Using a sample of 302 cisgender college students from across the United States, hierarchical multiple regressions on bootstrap samples were used to analyze how these factors are associated with anti-trans attitudes and behaviors. More liberal political beliefs, affiliation with more LGBTQ friends and family members, and less traditional gender role beliefs were related to more positive attitudes toward transgender people. Less traditional gender role beliefs and more positive attitudes were associated with more positive reported behaviors toward transgender individuals. Interventions designed to challenge traditional gender role beliefs and approximate affiliation with LGBTQ persons may be most effective to reduce pervasive hetero-cis-normative prejudice and discrimination within schools.

Substituted diaryl ether compounds as retinoic acid-related orphan Receptor-γt (RORγt) agonists.

The discovery of a series of substituted diarylether compounds as retinoic acid related orphan receptor γt (RORγt) agonists is described. Compound 1 was identified from deck mining as a RORγt agonist. Hit-to-lead optimization led to the identification of lead compound 5, which possesses improved potency (10x). Extensive SAR exploration led to the identification of a potent and selective compound 22, that demonstrated an improved pharmacokinetic profile and a dose-dependent pharmacodynamic response. However, when dosed in a MC38 syngeneic tumor model, no evidence of efficacy was observed. ©2020 Elsevier Science Ltd. All rights reserved.

Percutaneous Versus Surgical Revascularization for Acute Myocardial Infarction.

INTRODUCTION: Acute myocardial infarction (AMI) is a common medical condition in our clinical practice that should be treated with appropriate revascularization in a timely manner. Percutaneous revascularization (PR) has been the first-line treatment option when feasible. Limited data is available comparing PR to surgical revascularization (SR) in the AMI setting. METHODS: Study population was extracted from the 2016 Nationwide Readmissions Data using International Classification of Diseases, tenth edition, clinical modifications/procedure coding system codes for AMI, PR, SR, and procedural complications. Study endpoints included in-hospital all-cause mortality, length of index hospital stay (LOS), stroke, acute kidney injury, bleeding, need for blood transfusion, acute respiratory failure, and total hospital charges. RESULTS: The study identified 45,539 discharges with a principal admission diagnosis of AMI (38.7% ST elevation and 61.3% non-ST elevation) who had either PR or SR as a principal procedure (79.1% PR versus 20.9% SR). Single vessel revascularization was performed in 67.8% (93.1% had PR versus 6.9% had SR, p < 0.01). Multivessel revascularization was performed in 32.2% (64.8% had PR versus 35.2% had SR, p < 0.01). 83% of SR was in the setting of non-ST elevation AMI (NSTEMI). In comparison to SR, PR was associated with higher in-hospital all-cause mortality (3.7% versus 2.2%, p < 0.01), shorter LOS (4.3 versus 11.6 days, p < 0.01), and lower incidence of post-procedural stroke (1.0% versus 1.8%, p < 0.01), acute kidney injury (14.9% versus 24.8%, p < 0.01), bleeding (4.3% versus 47.1%, p < 0.01), need for blood transfusion (2.9% versus 18.5%, p < 0.01), acute respiratory failure (10.7% versus 19.8%, p < 0.01), and total hospital charges (120,590$ versus 229,917$, p < 0.01). These results persist after adjustment for baseline characteristics. In a subgroup analysis, SR mortality benefit persisted in patients who had multivessel revascularization (in both ST and non-ST elevation AMI), but not in single vessel revascularization. CONCLUSIONS: In patients presented with AMI, PR was associated with higher in-hospital all-cause mortality but lower morbidity, shorter LOS, and lower total hospital charges than SR. However, the mortality benefit of SR was seen in multivessel revascularization only, and not in single vessel revascularization.

Strain-Controlled Superconductivity in Few-Layer NbSe2.

The controlled tunability of superconductivity in low-dimensional materials may enable new quantum devices. Particularly in triplet or topological superconductors, tunneling devices such as Josephson junctions, etc., can demonstrate exotic functionalities. The tunnel barrier, an insulating or normal material layer separating two superconductors, is a key component for the junctions. Thin layers of NbSe2 have been shown as a superconductor with strong spin orbit coupling, which can give rise to topological superconductivity if driven by a large magnetic exchange field. Here we demonstrate the superconductor-insulator transitions in epitaxially grown few-layer NbSe2 with wafer-scale uniformity on insulating substrates. We provide the electrical transport, Raman spectroscopy, cross-sectional transmission electron microscopy, and X-ray diffraction characterizations of the insulating phase. We show that the superconductor-insulator transition is driven by strain, which also causes characteristic energy shifts of the Raman modes. Our observation paves the way for high-quality heterojunction tunnel barriers to be seamlessly built into epitaxial NbSe2 itself, thereby enabling highly scalable tunneling devices for superconductor-based quantum electronics.

Absence of OATP1B (Organic Anion-Transporting Polypeptide) Induction by Rifampin in Cynomolgus Monkeys: Determination Using the Endogenous OATP1B Marker Coproporphyrin and Tissue Gene Expression.

Organic anion-transporting polypeptide (OATP) 1B induction is an evolving mechanism of drug disposition and interaction. However, there are contradictory reports describing OATP1B expression in hepatocytes and liver biopsies after administration of an inducer. This study investigated the in vivo effects of the common inducer rifampin (RIF) on the activity and expression of cynomolgus monkey OATP1B1 and OATP1B3 transporters, which are structurally and functionally similar their human OATP1B counterparts. Multiple doses of oral RIF (15 mg/kg) resulted in a steady 3.9-fold increase of CYP3A biomarker, 4ß-hydroxycholesterol (4ßHC), in the plasma samples collected before each RIF dose during the treatment period (i.e., predose). In contrast, the predose plasma levels of OATP1B biomarkers coproporphyrin (CP) I and CPIII did not change when compared with RIF treatment. The trough concentration, area under plasma concentration-time curve (AUC), and half-life of RIF decreased markedly during RIF treatment, suggesting that RIF induced its own clearance. Consequently, RIF treatment increased CPI and CPIII AUCs substantially after a single administration and, to a lesser extent, after multiple administrations compared with preadministration AUCs. In addition, OATP1B1 and OATP1B3 mRNA expressions were not modulated by RIF treatment (0.85-1.3-fold), whereas CYP3A8 expression was increased 3.7-5.0-fold, which correlated well with the predose levels of CP and 4ßHC. Rifampin treatment showed 2.0-3.3-fold increases in P-glycoprotein (P-gp), breast cancer resistance protein (BCRP), and multidrug resistance-associated protein 2 (MRP2) expression in the small intestine. Collectively, these findings indicate that monkey OATP1B and OATP1B3 are not induced by RIF, and further investigation of OATP1B induction by RIF and other nuclear receptor activators in humans is warranted. SIGNIFICANCE STATEMENT: In this study, combined endogenous biomarker and gene expression data suggested that RIF did not induce OATP1B in cynomolgus monkeys. For the first time, the study determines transporter gene expression in the nonhuman primate liver, gut, and kidney tissues after administration of RIF for 7 days, leading to a better understanding of the induction of OATP1B and other major drug transporters. Finally, it provides evidence to strengthen the claim that coproporphyrin is a suitable endogenous probe of OATP1B activity.

Substituted benzyloxytricyclic compounds as retinoic acid-related orphan receptor gamma t (RORγt) agonists.

Substituted benzyloxy aryl compound 2 was identified as an RORγt agonist. Structure based drug design efforts resulted in a potent and selective tricyclic compound 19 which, when administered orally in an MC38 mouse tumor model, demonstrated a desired pharmacokinetic profile as well as a dose-dependent pharmacodynamic response. However, no perceptible efficacy was observed in this tumor model at the doses investigated.