Digital health literacy and digital engagement for people with severe mental ill health across the course of the COVID-19 pandemic in England.

BACKGROUND: An unprecedented acceleration in digital mental health services happened during the COVID-19 pandemic. However, people with severe mental ill health (SMI) might be at risk of digital exclusion, partly because of a lack of digital skills, such as digital health literacy. The study seeks to examine how the use of the Internet has changed during the pandemic for people with SMI, and explore digital exclusion, symptomatic/health related barriers to internet engagement, and digital health literacy. METHODS: Over the period from July 2020 to February 2022, n = 177 people with an SMI diagnosis (psychosis-spectrum disorder or bipolar affective disorder) in England completed three surveys providing sociodemographic information and answering questions regarding their health, use of the Internet, and digital health literacy. RESULTS: 42.5% of participants reported experiences of digital exclusion. Cochrane-Q analysis showed that there was significantly more use of the Internet at the last two assessments (80.8%, and 82.2%) compared to that at the beginning of the pandemic (65.8%; ps < 0.001). Although 34.2% of participants reported that their digital skills had improved during the pandemic, 54.4% still rated their Internet knowledge as being fair or worse than fair. Concentration difficulties (62.6%) and depression (56.1%) were among the most frequently reported symptomatic barriers to use the Internet. The sample was found to have generally moderate levels of digital health literacy (M = 26.0, SD = 9.6). Multiple regression analysis showed that higher literacy was associated with having outstanding/good self-reported knowledge of the Internet (ES = 6.00; 95% CI: 3.18-8.82; p < .001), a diagnosis of bipolar disorder (compared to psychosis spectrum disorder - ES = 5.14; 95% CI: 2.47-7.81; p < .001), and being female (ES = 3.18; 95% CI: 0.59-5.76; p = .016). CONCLUSIONS: These findings underline the need for training and support among people with SMI to increase digital skills, facilitate digital engagement, and reduce digital engagement, as well as offering non-digital engagement options to service users with SMI.

US Army basic combat training alters the relationship between body mass index and per cent body fat.

INTRODUCTION/BACKGROUND: As a proxy for adiposity, body mass index (BMI) provides a practical public health metric to counter obesity-related disease trends. On an individual basis, BMI cannot distinguish fat and lean components of body composition. Further, the relationship between BMI and body composition may be altered in response to physical training. We investigated this dynamic relationship by examining the effect of US Army basic combat training (BCT) on the association between BMI and per cent body fat (%BF). METHODS: BMI and %BF were measured at the beginning (week 1) and end (week 9) of BCT in female (n=504) and male (n=965) trainees. Height and weight were obtained for BMI, and body composition was obtained by dual X-ray absorptiometry. Sensitivity and specificity of BMI-based classification were determined at two BMI thresholds (25 kg/m2 and 27.5 kg/m2). RESULTS: A progressive age-related increase in fat-free mass index (FFMI) was observed, with an inflection point at age 21 years. In soldiers aged 21+, BMI of 25.0 kg/m2 predicted 33% and 29% BF in women and 23% and 20% BF in men and BMI of 27.5 kg/m2 predicted 35% and 31% BF in women and 26% and 22% BF in men, at the start and end of BCT, respectively. Sensitivity and specificity of BMI-based classification of %BF were poor. Soldiers below BMI of 20 kg/m2 had normal instead of markedly reduced %BF, reflecting especially low FFMI. CONCLUSIONS: BCT alters the BMI-%BF relationship, with lower %BF at a given BMI by the end of BCT compared with the beginning, highlighting the unreliability of BMI to try to estimate body composition. The specific BMI threshold of 25.0 kg/m2, defined as 'overweight', is an out-of-date metric for health and performance outcomes. To the extent that %BF reflects physical readiness, these data provide evidence of a fit and capable military force at BMI greater than 25.0 kg/m2.

Analysis of rare disruptive germline mutations in 2135 enriched BRCA-negative breast cancers excludes additional high-impact susceptibility genes.

BACKGROUND: Breast cancer has a significant heritable basis, of which ∼60% remains unexplained. Testing for BRCA1/BRCA2 offers useful discrimination of breast cancer risk within families, and identification of additional breast cancer susceptibility genes could offer clinical utility. PATIENTS AND METHODS: We included 2135 invasive breast cancer cases recruited via the Breast and Ovarian Cancer Susceptibility study, a retrospective UK study of familial breast cancer. ELIGIBILITY CRITERIA: female, BRCA-negative, white European ethnicity, and one of: (i) breast cancer family history, (ii) bilateral disease, (iii) young age of onset (<30 years), and (iv) concomitant ovarian cancer. We undertook exome sequencing of cases and carried out gene-level burden testing of rare damaging variants against those from 51 377 ethnicity-matched population controls from gnomAD. RESULTS: 159/2135 (7.4%) cases had a qualifying variant in an established breast cancer susceptibility gene, with minimal evidence of signal in other cancer susceptibility genes. Known breast cancer susceptibility genes PALB2, CHEK2, and ATM were the only genes to retain statistical significance after correcting for multiple testing. Due to the enrichment of hereditary cases in the series, we had good power (>80%) to detect a gene of BRCA1-like risk [odds ratio (OR) = 10.6] down to a population minor allele frequency of 4.6 × 10-5 (1 in 10 799, less than one-tenth that of BRCA1)and of PALB2-like risk (OR = 5.0) down to a population minor allele frequency of 2.8 × 10-4 (1 in 1779, less than half that of PALB2). Power was lower for identification of novel moderate penetrance genes (OR = 2-3) like CHEK2 and ATM. CONCLUSIONS: This is the largest case-control whole-exome analysis of enriched breast cancer published to date. Whilst additional breast cancer susceptibility genes likely exist, those of high penetrance are likely to be of very low mutational frequency. Contention exists regarding the clinical utility of such genes.

Measuring the digital divide among people with severe mental ill health using the essential digital skills framework.

AIMS: Amid the vast digitalisation of health and other services during the pandemic, people with no digital skills are at risk of digital exclusion. This risk might not abate by the end of the pandemic. This article seeks to understand whether people with severe mental ill health (SMI) have the necessary digital skills to adapt to these changes and avoid digital exclusion. METHODS: Two hundred and forty-nine adults with SMI across England completed a survey online or offline. They provided information on their digital skills based on the Essential Digital Skills (EDS) framework, sociodemographic information, and digital access. This is the first time that the EDS is benchmarked in people with SMI. RESULTS: 42.2% had no Foundation Skills, and 46.2% lacked skills for daily life (lacking Foundation or Life Skills). 23.0% of those working lacked skills for professional life (lacking Foundation or Work Skills). The most commonly missing skills were handling passwords and using the device settings (Foundation Skills) and online problem solving (Skills for Life). People were interested in learning more about approximately half of the skills they did not have. People were more likely to lack Foundation Skills if they were older, not in employment, had a psychosis-spectrum disorder, or had no Internet access at home. CONCLUSION: A significant portion of people with SMI lacked Foundation Skills in this objective and benchmarked survey. This points to a high risk for digital exclusion and the need for focused policy and tailored health sector support to ensure people retain access to key services and develop digital skills and confidence. To our knowledge, this is the first time this has been described using the EDS framework. Services, including the National Health Service (NHS), need to be aware of and mitigate the risks.

Prevalence of Rh, Kell, Kidd, Duffy, and MNS antigens in the Hispanic donor population of South Texas.

As population diversity in the United States expands, understanding antigen prevalence by ethnic group is essential. Differences in antigen prevalence among ethnicities have caused increased alloimmunization in chronically transfused patients. Recognizing these differences in patients and donors can reduce the risk of patients developing alloantibodies. Also, determining the antigen prevalence by ethnicity will improve the ability of blood centers to have compatible blood available. Thus far, there has not been significant published data on antigen prevalence of the U.S. Hispanic population. A retrospective cross-sectional study was performed to determine the prevalence of red blood cell (RBC) antigens, as determined by human erythrocyte antigen genotyping, in South Texas Hispanic blood donors. A total of 3455 donors, seen from 1 January 2015 to 31 May 2020, were included in the study. These donors met the inclusion criteria of self-selecting Hispanic ethnicity and successfully donating a RBC component. The antigen results for each included donor were entered into a data collection spreadsheet. The prevalence of each antigen was calculated. A binomial test was performed to determine if the observed results are statistically different as compared with the published prevalence of antigens in white and black populations. After statistical analysis, the p value for most antigens was statistically significant (p < 0.05). The Kidd blood group antigens were the only major antigens that did not show a significant difference. Cohen's h showed a large effect size for most antigens when compared with those of the black population and a small to medium effect size when compared with those of the white population. For most blood groups antigens, their prevalence in Hispanic donors was significantly different than that published for both white and black populations.

Thermoneutrality induces vascular dysfunction and impaired metabolic function in male Wistar rats: a new model of vascular disease.

OBJECTIVE: Cardiovascular disease is of paramount importance, yet there are few relevant rat models to investigate its pathology and explore potential therapeutics. Housing at thermoneutral temperature (30 °C) is being employed to humanize metabolic derangements in rodents. We hypothesized that housing rats in thermoneutral conditions would potentiate a high-fat diet, resulting in diabetes and dysmetabolism, and deleteriously impact vascular function, in comparison to traditional room temperature housing (22 °C). METHODS: Male Wistar rats were housed at either room temperature or thermoneutral temperatures for 16 weeks on either a low or high-fat diet. Glucose and insulin tolerance tests were conducted at the beginning and end of the study. At the study's conclusion, vasoreactivity and mitochondrial respiration of aorta and carotid were conducted. RESULTS: We observed diminished vasodilation in vessels from thermoneutral rats ( P  < 0.05), whereas high-fat diet had no effect. This effect was also observed in endothelium-denuded aorta in thermoneutral rats ( P  < 0.05). Vasoconstriction was significantly elevated in aorta of thermoneutral rats ( P  < 0.05). Diminished nitric oxide synthase activity and nitrotyrosine, and elevated glutathione activity were observed in aorta from rats housed under thermoneutral conditions, indicating a climate of lower nitric oxide and excess reactive oxygen species in aorta. Thermoneutral rat aorta also demonstrated less mitochondrial respiration with lipid substrates compared with the controls ( P  < 0.05). CONCLUSION: Our data support that thermoneutrality causes dysfunctional vasoreactivity, decreased lipid mitochondrial metabolism, and modified cellular signaling. These are critical observations as thermoneutrality is becoming prevalent for translational research models. This new model of vascular dysfunction may be useful for dissection of targetable aspects of cardiovascular disease and is a novel and necessary model of disease.

Long-term effectiveness of Self-Help Plus in refugees and asylum seekers resettled in Western Europe: 12-month outcomes of a randomised controlled trial.

AIMS: As refugees and asylum seekers are at high risk of developing mental disorders, we assessed the effectiveness of Self-Help Plus (SH + ), a psychological intervention developed by the World Health Organization, in reducing the risk of developing any mental disorders at 12-month follow-up in refugees and asylum seekers resettled in Western Europe. METHODS: Refugees and asylum seekers with psychological distress (General Health Questionnaire-12 ⩾ 3) but without a mental disorder according to the Mini International Neuropsychiatric Interview (M.I.N.I.) were randomised to either SH + or enhanced treatment as usual (ETAU). The frequency of mental disorders at 12 months was measured with the M.I.N.I., while secondary outcomes included self-identified problems, psychological symptoms and other outcomes. RESULTS: Of 459 participants randomly assigned to SH + or ETAU, 246 accepted to be interviewed at 12 months. No difference in the frequency of any mental disorders was found (relative risk [RR] = 0.841; 95% confidence interval [CI] 0.389-1.819; p-value = 0.659). In the per protocol (PP) population, that is in participants attending at least three group-based sessions, SH + almost halved the frequency of mental disorders at 12 months compared to ETAU, however so few participants and events contributed to this analysis that it yielded a non-significant result (RR = 0.528; 95% CI 0.180-1.544; p-value = 0.230). SH + was associated with improvements at 12 months in psychological distress (p-value = 0.004), depressive symptoms (p-value = 0.011) and wellbeing (p-value = 0.001). CONCLUSIONS: The present study failed to show any long-term preventative effect of SH + in refugees and asylum seekers resettled in Western European countries. Analysis of the PP population and of secondary outcomes provided signals of a potential effect of SH + in the long-term, which would suggest the value of exploring the effects of booster sessions and strategies to increase SH + adherence.

An online Sexual Health and Rehabilitation eClinic (TrueNTH SHAReClinic) for prostate cancer patients: a feasibility study.

PURPOSE: The primary objective was to determine the feasibility of implementing the TrueNTH SHAReClinic as a pan-Canadian sexual health and rehabilitation intervention for patients treated for localized prostate cancer. METHODS: The feasibility study was designed to evaluate the accessibility and acceptability of the intervention. Participants from five institutions across Canada were enrolled to attend one pre-treatment and five follow-up online clinic visits over 1 year following their prostate cancer (PC) treatment. RESULTS: Sixty-five patients were enrolled in the intervention. Website analytics revealed that 71% completed the intervention in its entirety, including the educational modules, with an additional 10% completing more than half of the intervention. Five thousand eighty-three views of the educational modules were made along with 654 views of the health library items. Over 1500 messages were exchanged between participants and their sexual health coaches. At 12 months, the intervention received an overall average participant rating of 4.1 out of 5 on a single item satisfaction measure. CONCLUSION: Results support the TrueNTH SHAReClinic as highly acceptable to participants as defined by intervention adherence and engagement. The TrueNTH SHAReClinic demonstrated promise for being a feasible and potentially resource-efficient approach to effectively improving the sexual well-being of patients after PC treatment.

Midwifery students' perspectives of physical and virtual mobility activities including preferences for e-learning: A cross-sectional survey.

BACKGROUND: Contemporary higher education requires that all midwifery students have insight and understanding of global health practice and demonstrate intercultural sensitivity. However, the mobility models currently offered do not often fit the lives of large numbers of midwifery students. OBJECTIVES: To investigate midwifery students' international physical mobility activities and factors that affect mobility; to determine midwifery students' learning needs and preferences for related e-learning packages. DESIGN: Multi-centre, descriptive quantitative survey. SETTINGS: Four European Higher Education Institutions based in the United Kingdom, Estonia, Italy and the Netherlands offering an undergraduate midwifery programme. PARTICIPANTS: The sample included 205 midwifery students from Italy (n = 93), the Netherlands (n = 51); United Kingdom (n = 35) and Estonia (n = 26). METHODS: Data were collected in June-July 2020 through an online cross-sectional, bespoke questionnaire and analysed using summary statistical analysis. RESULTS: There is a high level of interest across a range of mobility opportunities, especially those of shorter duration. Barriers to mobility comprised finance, caring responsibilities, concerns about fitting mobility activities into the midwifery programme, negative impact on studies and language barriers. The most frequently identified facilitators of mobility included professional perspectives such as interest in other cultures and midwifery in other settings and an endorsement that mobility would add value to their development as a midwife. When engaging in virtual learning, the most preferred resources mentioned by the students were videos, video calls with peers, choice quiz and discussion forum. CONCLUSIONS: The barriers identified require new approaches to enable all midwifery students to benefit from transnational learning. The survey findings provide insights into midwifery students' perspectives from which a new mobility model can be developed.

Irradiation stability and induced ferromagnetism in a nanocrystalline CoCrCuFeNi highly-concentrated alloy.

In the field of radiation damage of crystalline solids, new highly-concentrated alloys (HCAs) are now considered to be suitable candidate materials for next generation fission/fusion reactors due to recently recorded outstanding radiation tolerance. Despite the preliminarily reported extraordinary properties, the mechanisms of degradation, phase instabilities and decomposition of HCAs are still largely unexplored fields of research. Herein, we investigate the response of a nanocrystalline CoCrCuFeNi HCA to thermal annealing and heavy ion irradiation in the temperature range from 293 to 773 K with the objective to analyze the stability of the nanocrystalline HCA in extreme conditions. The results led to the identification of two regimes of response to irradiation: (i) in which the alloy was observed to be tolerant under extreme irradiation conditions and (ii) in which the alloy is subject to matrix phase instabilities. The formation of FeCo monodomain nanoparticles under these conditions is also reported and a differential phase contrast study in the analytical electron-microscope is carried out to qualitatively probe its magnetic properties.

Sex-based differences in timely emergency department evaluations for patients with drug poisoning.

OBJECTIVES: Unintentional poisoning was the leading cause of injury-related death in the United States in 2017. Prescribed and illicit drugs are the most common cause of poisoning, and timely management in the emergency department (ED) is important. Our aim was to identify any disparities in wait times associated with sex for drug poisoning-related ED visits. STUDY DESIGN: We examined ED visits using data from the 2009-2017 National Hospital Ambulatory Medical Care Survey (NHAMCS). METHODS: Drug poisoning-related visits were identified using the International Classification of Diseases, Ninth or Tenth Revision, Clinical Modification codes. Delayed assessment was defined as wait times exceeding the recommended triage time. Weighted logistic regression was used. RESULTS: The average age was 36 years (standard error = 1.1), 54% female, 87% White and 29% had delayed assessment. Most common drugs were psychotropics (45%) and opioids (32%). Adjusting for race, payment source, urgency, multiple drug types and NSAIDs, females who had poisoning by substances other than opioids had 2.1 times higher likelihood of having a delayed assessment compared with males (odds ratio [95% confidence interval]: 2.1 [1.03-4.2]), although there was no difference between sexes among visits with opioid poisoning (P = 0.27). Neither race (P = 0.23) nor payment source (P = 0.22) were associated with delayed assessment, and the sex association was consistent across these groups. CONCLUSIONS: Females with non-opioid drug poisoning were more likely to have delayed assessment than men. None of the other demographic factors demonstrated a correlation. Identifying more populations vulnerable to delays in the ED can help guide the development of interventions and policies to expedite care and attenuate existing disparities.

Can NFL Combine Results be Used to Estimate NFL Defensive Players Longevity?

The National Football League Scouting Combine is an annual event held to evaluate football players. The results of the combine are used to identify talent and player potential. Our study aims to examine the relationship between combine drill performance (e.g., speed, power, agility, explosiveness) and career longevity. We performed a retrospective review of The National Football League combine test results for all defensive players from 2005-2015 to determine the association of each player's combine test results with career longevity. The position that had the most significant associations for 1-year status was linebackers, with weight, 10-yard dash, 20-yard dash, 40-yard dash, broad jump, 3-cone drill, and shuttle being significantly associated with 1-year roster status. The position that had the most significant associations for 5-year status was cornerbacks, with weight, 10-yard dash, 20-yard dash, 40-yard dash, 3-cone drill, and shuttle being significantly associated with 1-year roster status. The least number of significant associations was found for safeties, with no drill being associated with 1-year roster status and only height and shuttle time significantly associated with 5-year career longevity. Our study demonstrates the utility of the combine results to help estimate the career longevity of NFL defensive players.

Autologous Calvarial Bone Remodeling Technique for Small to Medium-Sized Cranial Defects in Young Children: The "Switch-Cranioplasty" Technique.

INTRODUCTION: Reconstruction of cranial defects in children less than 2 years of age, particularly when there is an associated dural defect, is challenging due to the need to accommodate active skull growth, limited options for autologous bone graft and thin calvarial bones. We use a simple remodeling technique that exploits the normal dura's inherent potential for new bone growth while covering the dural defect with adjacent skull. CASE PRESENTATION: We describe an alternating, two-piece craniotomy or "switch-cranioplasty technique" to repair an occipital meningocele. The two pieces of craniotomy bone flap created around the existing skull and dural defect are switched in the horizontal plane in order to cover the site of the defect and the abnormal dura of the meningocele closure. The area of the original skull defect is transposed laterally over the normal dura. The healing of the lateral skull defects is facilitated with autologous bone chips and dust and covered by periosteal flaps that stimulate spontaneous re-ossification. DISCUSSION: The advantages of this technique are the use of autologous bone adjacent to the skull defect, incorporation of the autologous bone into the growing skull, an acceptable cosmetic and functional outcome in a simple manner. The indications can be extended to include small to medium-sized calvarial defects secondary to leptomeningeal cyst and trauma.

High-Resolution Laser-Induced Graphene from Photoresist.

The fabrication of patterned graphene electronics at high resolution is an important challenge for many applications in microelectronics. Here, we demonstrate the conversion of positive photoresist (PR), commonly employed in the commercial manufacture of consumer electronics, into laser-induced graphene (LIG). Sequential lasing converts the PR photopolymer first into amorphous carbon, then to photoresist-derived LIG (PR-LIG). The resulting material possesses good conductivity and is easily doped with metal or other additives for additional functionality. Furthermore, photolithographic exposure of PR prior to lasing enables the generation of PR-LIG patterns small enough to be invisible to the naked eye. By exploiting PR as a photopatternable LIG precursor, PR-LIG can be synthesized with a spatial resolution of ∼10 µm, up to 15 times smaller than conventional LIG patterning methods. The patterning of these small PR-LIG features could offer a powerful and broadly accessible strategy for the fabrication of microscale LIG-derived nanocomposites for on-chip devices.

Evaluation of the Neonatal Sequential Organ Failure Assessment and Mortality Risk in Preterm Infants With Late-Onset Infection.

Importance: Infection in neonates remains a substantial problem. Advances for this population are hindered by the absence of a consensus definition for sepsis. In adults, the Sequential Organ Failure Assessment (SOFA) operationalizes mortality risk with infection and defines sepsis. The generalizability of the neonatal SOFA (nSOFA) for neonatal late-onset infection-related mortality remains unknown. Objective: To determine the generalizability of the nSOFA for neonatal late-onset infection-related mortality across multiple sites. Design, Setting, and Participants: A multicenter retrospective cohort study was conducted at 7 academic neonatal intensive care units between January 1, 2010, and December 31, 2019. Participants included 653 preterm (<33 weeks) very low-birth-weight infants. Exposures: Late-onset (>72 hours of life) infection including bacteremia, fungemia, or surgical peritonitis. Main Outcomes and Measures: The primary outcome was late-onset infection episode mortality. The nSOFA scores from survivors and nonsurvivors with confirmed late-onset infection were compared at 9 time points (T) preceding and following event onset. Results: In the 653 infants who met inclusion criteria, median gestational age was 25.5 weeks (interquartile range, 24-27 weeks) and median birth weight was 780 g (interquartile range, 638-960 g). A total of 366 infants (56%) were male. Late-onset infection episode mortality occurred in 97 infants (15%). Area under the receiver operating characteristic curves for mortality in the total cohort ranged across study centers from 0.71 to 0.95 (T0 hours), 0.77 to 0.96 (T6 hours), and 0.78 to 0.96 (T12 hours), with utility noted at all centers and in aggregate. Using the maximum nSOFA score at T0 or T6, the area under the receiver operating characteristic curve for mortality was 0.88 (95% CI, 0.84-0.91). Analyses stratified by sex or Gram-stain identification of pathogen class or restricted to infants born at less than 25 weeks' completed gestation did not reduce the association of the nSOFA score with infection-related mortality. Conclusions and Relevance: The nSOFA score was associated with late-onset infection mortality in preterm infants at the time of evaluation both in aggregate and in each center. These findings suggest that the nSOFA may serve as the foundation for a consensus definition of sepsis in this population.

A systematic review of the behaviours associated with depression in people with severe-profound intellectual disability.

The assessment of depression in people with severe to profound intellectual disability (severe-profound ID) is challenging, primarily due to inability to report internal states such as mood, feelings of worthlessness and suicidal ideation. This group also commonly presents with challenging behaviours (e.g. aggression and self-injury) with debate about whether these behaviours should be considered 'depressive equivalents' or are sensitive for, but not specific to, depression in severe-profound ID. We conducted a systematic review exploring behaviours associated with depression and low mood in individuals with severe-profound ID. The review was conducted in accordance with Preferred Reporting Items for Systematic Reviews and Meta-Analyses (2009) guidelines. Three electronic databases were searched (Embase, PsycINFO and Ovid MEDLINE), and 13 studies were included and rated for quality. Few studies were rated as having high methodological quality. Behaviours captured by standard diagnostic schemes for depression (e.g. Diagnostic and Statistical Manual of Mental Disorders and International Classification of Diseases) showed a relationship with depression in severe-profound ID, including the two core symptoms (depressed affect and anhedonia), as well as irritability, sleep disturbance, psychomotor agitation, reduced appetite and fatigue. Challenging behaviours such as aggression, self-injury, temper tantrums, screaming and disruptive behaviour were associated with depression. Challenging behaviours show a robust relationship with depression. Whilst these behaviours may suggest an underlying depression, study limitations warrant caution in labelling them as 'depressive equivalents'. These limitations include not controlling for potential confounds (autism, other affective disorders and pain) and bias associated with comparing depressed/non-depressed groups on the same behavioural criteria used to initially diagnose and separate these groups. Future studies that use depressive measures designed for ID populations, which control for confounds and which explore low mood irrespective of psychiatric diagnosis, are warranted to better delineate the behaviours associated with depression in this population (PROSPERO 2018: CRD42018103244).

Preclinical assessment of dual CYP26[A1/B1] inhibitor, DX308, as an improved treatment for keratinization disorders.

Background: Retinoid-based therapies are commonly used in the treatment of disorders of keratinization and other skin disorders but can result in non-specific effects and adverse reactions. Use of retinoic acid metabolism blocking agents (RAMBAs) such as DX308 may address these shortcomings. Objectives: Characterize the therapeutic potential of recently discovered, CYP26-selective RAMBA, DX308. Materials and Methods: Preliminary in vitro assessment of potential off-target activity, metabolic and toxicologic profiling. Studies to assess safety and efficacy of topical treatment in correcting abnormal skin morphology in rhino mice. Extensive gene expression profiling by RNA sequencing and qPCR in 3D epidermis grown with keratinocytes (KCs) from keratinization disorders and healthy controls, to investigate modulation of retinoid biopathways. Results: In vitro, DX308 does not interact with off-target nuclear receptors or CYP450s, is not genotoxic, and is stable in skin, despite vigorous hepatic metabolism. In vivo, topical DX308 induces comedolysis and epidermal thickening without apparent adverse effects. Gene expression profiling shows potent modulation of retinoid-responsive genes by DX308 in both healthy and keratinization disorder KCs. Pathway analysis suggests DX308 may inhibit inflammatory and immune responses in KCs. Conclusions: These preliminary studies suggest that DX308 is an efficacious topical therapeutic with a favourable metabolic and safety profiles. DX308 may present an improved therapeutic alternative for the treatment of keratinization disorders and other retinoid-responsive skin ailments.

Concomitant LATE-NC in Alzheimer's disease is not associated with increased tau or amyloid-ß pathological burden.

AIMS: Limbic-predominant age-related TDP-43 encephalopathy neuropathological change (LATE-NC) is present in approximately 50% of Alzheimer's disease (AD) cases and is associated with accelerated cognitive decline. Studies indicate a potential synergistic relationship between LATE-NC and hyperphosphorylated tau. It is unknown if LATE-NC is an independent driver of cognitive impairment or exerts its influence through synergistic relationships with tau. This cliniconeuropathological study investigated the impact of LATE-NC on quantified measures of AD-associated pathology and its impact on clinical measures. METHODS: A total of 61 AD cases underwent neuropathological assessment for LATE-NC and quantitative assessment [area covered by immunoreactivity (IR)] for early conformational tau (MC-1), late-stage hyperphosphorylated tau (AT8) and amyloid-ß in the amygdala and five neocortical regions. Clinical measures included age of disease onset, final Mini-Mental State Examination (MMSE) score and rate of cognitive decline. RESULTS: LATE-NC was present in 41 AD cases (AD/LATE-NC; 67.2%). No significant differences in MC-1-IR, AT8-IR or 4G8-IR were observed in any region between AD/LATE-NC and AD without LATE-NC, indicating no accelerated aggregation or hyperphosphorylation of tau proteins in the AD/LATE-NC cases. Final MMSE was significantly lower in AD/LATE-NC cases and was significantly associated with LATE-NC score even when controlled for the presence of both MC-1-IR and AT8-IR (P = 0.009). CONCLUSION: The presence of LATE-NC in AD is not associated with an increase in the burden of early or late tau or Aß pathology. LATE-NC is associated with a lower final MMSE score independent of tau pathology.

Irradiation-Induced Extremes Create Hierarchical Face-/Body-Centered-Cubic Phases in Nanostructured High Entropy Alloys.

A nanoscale hierarchical dual-phase structure is reported to form in a nanocrystalline NiFeCoCrCu high-entropy-alloy (HEA) film via ion irradiation. Under the extreme energy deposition and consequent thermal energy dissipation induced by energetic particles, a fundamentally new phenomenon is revealed, in which the original single-phase face-centered-cubic (FCC) structure partially transforms into alternating nanometer layers of a body-centered-cubic (BCC) structure. The orientation relationship follows the Nishiyama-Wasser-man relationship, that is, (011)BCC || ( 1¯1¯1)FCC and [100]BCC || [ 11¯0]FCC . Simulation results indicate that Cr, as a BCC stabilizing element, exhibits a tendency to segregate to the stacking faults (SFs). Furthermore, the high densities of SFs and twin boundaries in each nanocrystalline grain serve to accelerate the nucleation and growth of the BCC phase during irradiation. By adjusting the irradiation parameters, desired thicknesses of the FCC and BCC phases in the laminates can be achieved. This work demonstrates the controlled formation of an attractive dual-phase nanolaminate structure under ion irradiation and provides a strategy for designing new derivate structures of HEAs.

Knee Ligament Anatomy and Biomechanics.

An understanding of knee ligament anatomy and biomechanics is foundational for physicians treating knee injuries, especially the more rare and morbid multiligamentous knee injuries. This chapter examines the roles that the cruciate and collateral anatomy and morphology play in their kinematics. Additionally, the biomechanics of the ACL, PCL, MCL, and LCL are discussed as they have surgical and reconstructive implications.