Hierarchical Protofilament Intertwining Rules the Formation of Mixed-Curvature Amyloid Polymorphs.

Amyloid polymorphism is a hallmark of almost all amyloid species, yet the mechanisms underlying the formation of amyloid polymorphs and their complex architectures remain elusive. Commonly, two main mesoscopic topologies are found in amyloid polymorphs characterized by non-zero Gaussian and mean curvatures: twisted ribbons and helical fibrils, respectively. Here, a rich heterogeneity of configurations is demonstrated on insulin amyloid fibrils, where protofilament packing can occur, besides the common polymorphs, also in a combined mode forming mixed-curvature polymorphs. Through AFM statistical analysis, an extended array of heterogeneous architectures that are rationalized by mesoscopic theoretical arguments are identified. Notably, an unusual fibrillization pathway is also unraveled toward mixed-curvature polymorphs via the widespread recruitment and intertwining of protofilaments and protofibrils. The results present an original view of amyloid polymorphism and advance the fundamental understanding of the fibrillization mechanism from single protofilaments into mature amyloid fibrils.

Hypothalamic Transcriptome Response To Simulated Diel Earthen Pond Hypoxia Cycles In Channel Catfish (Ictalurus punctatus).

Commercial culture of channel catfish (Ictalurus punctatus) occurs in earthen ponds that are characterized by diel swings in dissolved oxygen concentration that can fall to severe levels of hypoxia which can suppress appetite and lead to suboptimal growth. Given the significance of the hypothalamus in regulating these processes in other fishes, an investigation into the hypothalamus transcriptome was conducted to identify specific genes and expression patterns responding to hypoxia. Channel catfish in normoxic water were compared to catfish subjected to 12 hours of hypoxia (20% oxygen saturation; 1.8 mg O2/L; 27 °C) followed by 12 hours of recovery in normoxia to mimic 24-hours in a catfish aquaculture pond. Fish were sampled at 0-, 6-, 12-, 18-, and 24-hour time points, with the 6- and 12-hour samplings occurring during hypoxia. A total of 190 genes were differentially expressed during the experiment, with most occurring during hypoxia and returning to baseline values within 6 hours of normoxia. Differentially expressed genes were sorted by function into Gene Ontology biological processes and revealed that most were categorized as "response to hypoxia", "sprouting angiogenesis", and "cellular response to xenobiotic stimulus". The patterns of gene expression reported here suggest that transcriptome responses to hypoxia are broad and quickly reversibly with the onset of normoxia. Although no genes commonly reported to modulate appetite were found to be differentially expressed in this experiment, several candidates were identified for future studies investigating the interplay between hypoxia and appetite in channel catfish, including adm, igfbp1a, igfbp7, and stc2b.

Demographic and mental health profile of youth in a gender service: An African case series.

Background: Despite a massive global increase in research on gender-diverse youth, there have been no studies in Africa on gender-diverse children and adolescents presenting to health services. Aim: This study aimed to present the first African findings of the demographic and mental health profile of youth who have presented at a gender service in South Africa. Setting: A specialist mental health outpatient service, consisting of psychiatry, psychology and nursing input, for gender-diverse child and adolescent patients in the Western Cape. Methods: All consenting youth seen at a gender service, consisting of psychiatry, psychology and nursing input, in state and by the same clinician in private practice between January 2012 and May 2019 were participants of a retrospective, sequential case series study. Data of interest, including gender identity and sexuality, mental health history and social information, were extracted from the psychiatry files of participants. Results: Thirty-nine participants were part of the registry and qualified for the study: 72% self-identified as white, 15% as coloured and 13% as black African. The rate of co-occurring psychopathology was high (64%) and included high rates of autism, particularly in trans males (26%), suicidal ideation in 31% and a history of suicide attempt(s) in 10%. Conclusions: This first study describing gender-diverse youth seeking support relating to their gender identity in Africa showed they had remarkable similarities to those studied internationally. Contribution: Establishing that transgender youth of all major racial groups in the province with similar demographic profiles to other parts of the world are presenting to services in South Africa and in need of mental health support and interventions.

Trends in Neosubstrate Degradation by Cereblon-Based Molecular Glues and the Development of Novel Multiparameter Optimization Scores.

Molecular glues enable the degradation of previously "undruggable" proteins via the recruitment of cereblon (CRBN) to the target. One major challenge in designing CRBN E3 ligase modulating compounds (CELMoDs) is the selectivity profile toward neosubstrates, proteins recruited by CRBN E3 ligase agents for degradation. Common neosubstrates include Aiolos, Ikaros, GSPT1, CK1α, and SALL4. Unlike achieving potency and selectivity for traditional small molecule inhibitors, reducing the degradation of these neosubstrates is complicated by the ternary nature of the complex formed between the protein, CRBN, and CELMoD. The standard guiding principles of medicinal chemistry, such as enforcing hydrogen bond formation, are less predictive of degradation efficiency and selectivity. Disclosed is an analysis of our glutarimide CELMoD library to identify interpretable chemical features correlated to selectivity profiles and general cytotoxicity. Included is a simple multiparameter optimization function using only three parameters to predict whether molecules will have undesired neosubstrate activity.

Effects of policies or interventions that influence the school food environment on children's health and nonhealth outcomes: a systematic review.

CONTEXT: Globally, 1 in 3 children under 5 years is undernourished or overweight, and 1 in 2 suffers from hidden hunger due to nutrient deficiencies. As children spend a considerable time at school, school-based policies that aim to improve children's dietary intake may help address this double burden of malnutrition. OBJECTIVE: This systematic review aimed to assess the effects of implementing policies or interventions that influence the school food environment on children's health and nonhealth outcomes. DATA SOURCES, EXTRACTION, AND ANALYSIS: Eleven databases were searched up to April 2020 and the World Health Organization (WHO) released a call for data due in June 2020. Records were screened against the eligibility criteria, and data extraction and risk-of-bias assessment were conducted by 1 reviewer and checked by another. The synthesis was based on effect direction, and certainty of evidence was assessed using the GRADE (Grading of Recommendations Assessment, Development and Evaluation) approach. CONCLUSIONS: Seventy-four studies reporting 10 different comparisons were included. The body of evidence indicates that interventions addressing the school food environment may have modest beneficial effects on certain key outcomes. Nutrition standards for healthy foods and beverages at schools, interventions that change how food is presented and positioned, and fruit and vegetable provision may have a beneficial effect on the consumption of healthy foods and beverages. Regarding effects on the consumption of discretionary foods and beverages, nutrition standards may have beneficial effects. Nutrition standards for foods and beverages, changes to portion size served, and the implementation of multiple nudging strategies may have beneficial effects on energy intake. Regarding effects of purchasing or selecting healthier foods, changes to how food is presented and positioned may be beneficial. This review was commissioned and supported by the WHO (registration 2020/1001698-0). WHO reviewed and approved the protocol for the systematic review and reviewed the initial report of the completed systematic review. SYSTEMATIC REVIEW REGISTRATION: PROSPERO registration no: CRD42020186265.

Association of Cerebrovascular Imaging Biomarkers, Depression, and Anxiety, with Mild Cognitive Impairment.

The study included 1,738 Mayo Clinic Study of Aging participants (≥50 years old; 1,460 cognitively unimpaired and 278 with mild cognitive impairment (MCI)) and examined the cross-sectional association between cerebrovascular (CVD) imaging biomarkers (e.g., white matter hyperintensities (WMH), infarctions) and Beck Depression Inventory-II (BDI-II) and Beck Anxiety Inventory (BAI) scores, as well as their association with MCI. High (abnormal) WMH burden was significantly associated with having BDI-II>13 and BAI > 7 scores, and both (CVD imaging biomarkers and depression/anxiety) were significantly associated with MCI when included simultaneously in the model, suggesting that both were independently associated with the odds of MCI.

Effect of hypoxia duration and pattern on channel Catfish (Ictalurus punctatus) neuropeptide gene expression and hematology.

Commercial aquaculture production of channel catfish (Ictalurus punctatus) occurs in shallow ponds with daily cycling of dissolved oxygen concentration ranging from supersaturation to severe hypoxia. Once daily minimum dissolved oxygen concentration falls below 3.0 mg O2/L, channel catfish have a reduced appetite, leading to reduced growth rates. In other fishes, upregulation of the neuropeptides corticotropin-releasing factor (CRF) and urotensin I (UI) have been implicated as initiating the mechanism responsible for decreasing appetite once an environmental stressor is detected. Channel catfish maintained at 27 °C in aquaria were subjected to varying durations and patterns of hypoxia (1.75 ± 0.07 mg O2/L) to evaluate underlying physiological responses to hypoxia and determine if hypothalamic CRF and UI are responsible for hypoxia-induced anorexia in channel catfish. During a short exposure to hypoxia (12 h), venous PO2 was significantly lower within 6 h and was coupled with an increase of hematocrit and decrease of blood osmolality, yet all responses reversed within 12 h after returning to normoxia. When this pattern of hypoxia and normoxia was repeated cyclically for 5 days, these physiological responses repeated daily. Extended periods of hypoxia (5 days) resulted in similar hematological responses, which did not recover to baseline values during the hypoxia exposure. This study did not find a significant change in hypothalamic transcription of CRF and UI during hypoxia challenges but did identify multiple physiological adaptive responses that work together to reduce the severity of experimentally induced hypoxia in channel catfish.

"A turn in the road, but still a rough journey" - Parent and child perspectives of outcomes after pre-adolescent inpatient psychiatric admission.

BACKGROUND: Research regarding the outcomes of child and adolescent psychiatric inpatients appears insufficient and neglected. Where data are available, the majority of studies focus on adolescents. This study aimed (a) to describe child and parental perspectives of short-, medium- and long-term outcomes of children who have had a pre-adolescent inpatient psychiatric admission, and (b) to analyse these dyadic experiential data to identify outcome variables of importance to families and service users that could be used in future outcomes-based research. METHODS: The study employed a qualitative methodology, using semi-structured in-depth interviews of ten parent-child dyads to (a) collect the perspectives of children who have had an inpatient psychiatric admission at a pre-adolescent unit and their parents, and (b) to analyse the experiences of inpatient admission and perceived outcomes after discharge using thematic analysis. RESULTS: Overall, inpatient psychiatric admission was viewed as a positive and empowering experience by parents and children. Clear short-term benefits were reported as a result of new diagnoses, medications and new skills gained through the admission process. More than half of parent-child dyads reported long-term benefits, but many families commented on ongoing challenges. Thematic analysis identified diagnostic certainty, acquisition of cognitive and behavioural skills, appropriate educational environment, peer relationships, sustained follow-up and medication management, and parent-child relationships, as important contributors to outcomes. Importantly, the presence or lack of these elements influenced outcomes. CONCLUSIONS: The study explored parent-child dyadic perspectives about their experiences of inpatient mental health admissions for pre-adolescents and perceived outcomes after admission. The majority of families found inpatient admission positive and helpful, and thematic analysis identified a number of functional variables that may predict outcome. However, positive outcomes were associated with ongoing difficulties over time, as indicated by the theme "a turn in the road, but still a rough journey".

Impact of e-ASPECTS software on the performance of physicians compared to a consensus ground truth: a multi-reader, multi-case study.

Background: The Alberta Stroke Program Early CT Score (ASPECTS) is used to quantify the extent of injury to the brain following acute ischemic stroke (AIS) and to inform treatment decisions. The e-ASPECTS software uses artificial intelligence methods to automatically process non-contrast CT (NCCT) brain scans from patients with AIS affecting the middle cerebral artery (MCA) territory and generate an ASPECTS. This study aimed to evaluate the impact of e-ASPECTS (Brainomix, Oxford, UK) on the performance of US physicians compared to a consensus ground truth. Methods: The study used a multi-reader, multi-case design. A total of 10 US board-certified physicians (neurologists and neuroradiologists) scored 54 NCCT brain scans of patients with AIS affecting the MCA territory. Each reader scored each scan on two occasions: once with and once without reference to the e-ASPECTS software, in random order. Agreement with a reference standard (expert consensus read with reference to follow-up imaging) was evaluated with and without software support. Results: A comparison of the area under the curve (AUC) for each reader showed a significant improvement from 0.81 to 0.83 (p = 0.028) with the support of the e-ASPECTS tool. The agreement of reader ASPECTS scoring with the reference standard was improved with e-ASPECTS compared to unassisted reading of scans: Cohen's kappa improved from 0.60 to 0.65, and the case-based weighted Kappa improved from 0.70 to 0.81. Conclusion: Decision support with the e-ASPECTS software significantly improves the accuracy of ASPECTS scoring, even by expert US neurologists and neuroradiologists.

Describing whisker morphology of the Carnivora.

One of the largest ecological transitions in carnivoran evolution was the shift from terrestrial to aquatic lifestyles, which has driven morphological diversity in skulls and other skeletal structures. In this paper, we investigate the association between those lifestyles and whisker morphology. However, comparing whisker morphology over a range of species is challenging since the number of whiskers and their positions on the mystacial pads vary between species. Also, each whisker will be at a different stage of growth and may have incurred damage due to wear and tear. Identifying a way to easily capture whisker morphology in a small number of whisker samples would be beneficial. Here, we describe individual and species variation in whisker morphology from two-dimensional scans in red fox, European otter and grey seal. A comparison of long, caudal whiskers shows inter-species differences most clearly. We go on to describe global whisker shape in 24 species of carnivorans, using linear approximations of curvature and taper, as well as traditional morphometric methods. We also qualitatively examine surface texture, or the presence of scales, using scanning electron micrographs. We show that gross whisker shape is highly conserved, with whisker curvature and taper obeying simple linear relationships with length. However, measures of whisker base radius, length, and maybe even curvature, can vary between species and substrate preferences. Specifically, the aquatic species in our sample have thicker, shorter whiskers that are smoother, with less scales present than those of terrestrial species. We suggest that these thicker whiskers may be stiffer and able to maintain their shape and position during underwater sensing, but being stiffer may also increase wear.

Interactions Between Neuropsychiatric Symptoms and Alzheimer's Disease Neuroimaging Biomarkers in Predicting Longitudinal Cognitive Decline.

Objective: To examine interactions between Neuropsychiatric symptoms (NPS) with Pittsburgh Compound B (PiB) and fluorodeoxyglucose positron emission tomography (FDG-PET) in predicting cognitive trajectories. Methods: We conducted a longitudinal study in the setting of the population-based Mayo Clinic Study of Aging in Olmsted County, MN, involving 1581 cognitively unimpaired (CU) persons aged ≥50 years (median age 71.83 years, 54.0% males, 27.5% APOE ɛ4 carriers). NPS at baseline were assessed using the Neuropsychiatric Inventory Questionnaire (NPI-Q). Brain glucose hypometabolism was defined as a SUVR ≤ 1.47 (measured by FDG-PET) in regions typically affected in Alzheimer's disease. Abnormal cortical amyloid deposition was measured using PiB-PET (SUVR ≥ 1.48). Neuropsychological testing was done approximately every 15 months, and we calculated global and domain-specific (memory, language, attention, and visuospatial skills) cognitive z-scores. We ran linear mixed-effect models to examine the associations and interactions between NPS at baseline and z-scored PiB- and FDG-PET SUVRs in predicting cognitive z-scores adjusted for age, sex, education, and previous cognitive testing. Results: Individuals at the average PiB and without NPS at baseline declined over time on cognitive z-scores. Those with increased PiB at baseline declined faster (two-way interaction), and those with increased PiB and NPS declined even faster (three-way interaction). We observed interactions between time, increased PiB and anxiety or irritability indicating accelerated decline on global z-scores, and between time, increased PiB and several NPS (e.g., agitation) showing faster domain-specific decline, especially on the attention domain. Conclusions: NPS and increased brain amyloid deposition synergistically interact in accelerating global and domain-specific cognitive decline among CU persons at baseline.

Mid- and Late-Life Physical Activity and Neuropsychiatric Symptoms in Dementia-Free Older Adults: Mayo Clinic Study of Aging.

OBJECTIVE: This study examined associations between physical activity (PA) and neuropsychiatric symptoms (NPS) in older adults free of dementia. METHODS: This cross-sectional study included 3,222 individuals ≥70 years of age (1,655 men; mean±SD age=79.2±5.6; cognitively unimpaired, N=2,723; mild cognitive impairment, N=499) from the population-based Mayo Clinic Study of Aging. PA (taken as a presumed predictor) in midlife (i.e., when participants were 50-65 years of age) and late life (i.e., the year prior to assessment) was assessed with a self-reported, validated questionnaire; PA intensity and frequency were used to calculate composite scores. NPS (taken as presumed outcomes) were assessed with the Neuropsychiatric Inventory Questionnaire, Beck Depression Inventory (BDI-II), and Beck Anxiety Inventory (BAI). Regression analyses included midlife and late-life PA in each model, which were adjusted for age, sex, education, apolipoprotein E ɛ4 status, and medical comorbidity. RESULTS: Higher late-life PA was associated with lower odds of having apathy (OR=0.89, 95% CI=0.84-0.93), appetite changes (OR=0.92, 95% CI=0.87-0.98), nighttime disturbances (OR=0.95, 95% CI=0.91-0.99), depression (OR=0.94, 95% CI=0.90-0.97), irritability (OR=0.93, 95% CI=0.89-0.97), clinical depression (OR=0.92, 95% CI=0.88-0.97), and clinical anxiety (OR=0.90, 95% CI=0.86-0.94), as well as lower BDI-II (ß estimate=-0.042, 95% CI=-0.051 to -0.033) and BAI (ß estimate=-0.030, 95% CI=-0.040 to -0.021) scores. Higher midlife PA was associated only with higher BDI-II scores (ß estimate=0.011, 95% CI=0.004 to 0.019). Sex modified the associations between PA and NPS. CONCLUSIONS: Late-life PA was associated with a lower likelihood of clinical depression or anxiety and subclinical NPS. These findings need to be confirmed in a cohort study.

Reconstructive rhinoplasty using cadaver cartilage in relapsing polychondritis.

Relapsing polychondritis is a rare autoimmune disorder of unknown cause characterized by recurrent inflammation of cartilage predominantly affecting the ears, nose, and upper airway. The bridge of the nose and surrounding tissue can collapse, producing a saddle nose deformity. Nasal reconstruction is often challenging in these patients due to impaired wound healing and graft take caused by autoimmune inflammatory disease and prolonged immunosuppressant treatment. Many different reconstruction techniques like autologous rib, fascia lata, and calvarial bone grafts have been used. Herein we report the use of a cadaver cartilage graft in a 55-year-old woman with relapsing polychondritis and saddle nose deformity. Because of the characteristic chondritis of her autoimmune condition, cadaver cartilage was selected because it is antigenically different from the patient's own cartilage, offering significant structural integrity for nasal reconstruction compared to other techniques.

Health-related quality of life among people living with HIV in the era of universal test and treat: results from a cross-sectional study in KwaZulu-Natal, South Africa.

BACKGROUND: The World Health Organisation's (WHO) key population-based strategy for ending the human immunodeficiency virus (HIV) epidemic is universal HIV test and treat (UTT) along with pre-exposure prophylaxis (PrEP), and post-exposure prophylaxis (PEP). Despite the successful scale-up of the UTT strategy in sub-Saharan Africa (SSA), the quality of life (QoL) of people living with HIV (PLHIV) remains sub-optimal. Poor QoL in PLHIV may threaten the UNAIDS 95-95-95 programme targets. Monitoring QoL of PLHIV has become a key focus of HIV research among other outcomes so as to understand health-related QoL (HRQoL) profiles and identify interventions to improve programme performance. This study aimed to describe HRQoL profiles and identify their predictors in PLHIV in KwaZulu Natal, South Africa. METHODS: We conducted a secondary data analysis of a cross-sectional survey conducted between May and June 2022 among PLHIV (n = 105) accessing HIV services at an outpatient clinic in KwaZulu-Natal, South Africa. Socio-demographic, HRQoL (EQ-5D-5L index scores), clinical data, depressive symptoms (CES-D-10), and viral load data were collected from all participants. We examined predictors of HRQoL using generalised linear models controlling for age and sex. RESULTS: The mean age of the participants was 45 years (SD = 13). The proportion of participants with disabilities and comorbidities were 3% and 18%, respectively. Depressive symptoms were present in 49% of the participants. Participant's mean EQ-5D-5L index score was 0.87 (SD = 0.21) and ranged from 0.11 to 1.0. The mean general health state (EQ-VAS) was 74.7 (SD = 18.8) and ranged from 6 to 100. Factors that reduced HRQoL were disability (ß = -0.607, p ≤ 0.001), comorbidities (ß = - 0.23, p ≤ 0.05), presence of depressive symptoms (ß = -0.10, p ≤ 0.05), and old age (ß = -0.04, p ≤ 0.05). Factors that increased HRQoL were a good perceived health state (ß = 0.147, p ≤ 0.001) and availability of social support (ß = 0.098, p ≤ 0.05). CONCLUSION: A combination of old age (60 years and above), any disability and comorbidities had a considerable effect on HRQoL among PLHIV. Our findings support the recommendation for an additional fourth UNAIDS target that should focus on ensuring that 95% of PLHIV have the highest possible HRQoL. Psycho-social support interventions are recommended to improve the HRQoL of PLHIV.

Pearls & Oy-sters: Postpipeline Headache Phenomenon: Nummular Headache Presenting After Intracranial Aneurysm Stenting.

We report on a 31-year-old right-handed woman with a medical history of presyncopal episodes and migraine headaches who presented to the outpatient clinic with a nummular headache after intracerebral stenting, which was different than her previous migraines. This represents postpipeline embolization headache phenomenon, which is a relatively new term to describe a new or different headache in individuals who recently underwent intracranial vascular stenting as a treatment for cerebral aneurysms.

The possible effect of lactoferrin on the epigenetic characteristics of early mammalian embryos exposed to bisphenol A.

BACKGROUND: The main objective of this review was to state a hypothetical mechanism of the antitoxic effect of lactoferrin (Lf) on embryos exposed to bisphenol A (BPA). On this basis, it is possible to suggest Lf as a potential protective health component before conception upon toxic effects and viral infections. METHODS: The narrative review was performed using systematic review methods to identify relevant literature. The resources required for this study were obtained by searching the electronic database PubMed (MEDLINE). Articles were searched using the keywords "BPA," "lactoferrin," "DNA-methylation," "epigenetic," "mammals," "human," and "mouse." The inclusion criteria were as follows: (a) primary or original research; (b) study of epigenetic modification; and (c) study focuses on early mammalian development. RESULTS: Presented data demonstrate that Lf can modulate epigenetical characteristic, such as DNA methylation and reactive oxygen species (ROS), and, thereby, may serve as a potential readily available pharmaceutical product. CONCLUSION: Suggested hypothesis is based on the important interrelated role of changes in epigenetic modifications and oxidative stress in early embryogenesis under the influence of BPA and virus infection as a cause of the development of pathologies in the adult organism.

Internalizing problems, externalizing problems, and prosocial behavior - three dimensions of the strengths and difficulties questionnaire (SDQ): A study among South African adolescents.

This study aimed to examine the factor structure of the Strengths and Difficulties Questionnaire Self-Report version (SDQ-S), its psychometric properties and measurement invariance by gender and language spoken at home, among secondary school students in Western Cape, South Africa. A sample of 3,542 adolescents in Grade 8 (Mean age = 13.7 years) completed the SDQ-S in a three-language questionnaire (Afrikaans, English and isiXhosa). The data were collected from 42 secondary schools in Cape Town, South Africa. Confirmatory factor analyses with the WLSMV estimator with adjustment for cluster effects (schools) were applied. The SDQ-S was originally developed to cover five domains: four "difficulty" domains (hyperactivity/inattention, emotional, conduct, and peer) and one "strengths" domain (prosocial behavior). When the five factors were tested on the data for the current study, poor fit was obtained. After excluding four items, a three-factor solution with no cross-loadings and no correlated error terms obtained acceptable fit. The results are consistent with previous studies. Strong measurement invariance across genders and language spoken at home was confirmed. In studies of community samples, the use of the SDQ-S scale as an instrument with a three-factor dimension (internalizing, externalizing and prosocial) may be more appropriate than using the original five-factor model.