APOE4/4 is linked to damaging lipid droplets in Alzheimer's disease microglia.

Several genetic risk factors for Alzheimer's disease implicate genes involved in lipid metabolism and many of these lipid genes are highly expressed in glial cells1. However, the relationship between lipid metabolism in glia and Alzheimer's disease pathology remains poorly understood. Through single-nucleus RNA sequencing of brain tissue in Alzheimer's disease, we have identified a microglial state defined by the expression of the lipid droplet-associated enzyme ACSL1 with ACSL1-positive microglia being most abundant in patients with Alzheimer's disease having the APOE4/4 genotype. In human induced pluripotent stem cell-derived microglia, fibrillar Aß induces ACSL1 expression, triglyceride synthesis and lipid droplet accumulation in an APOE-dependent manner. Additionally, conditioned media from lipid droplet-containing microglia lead to Tau phosphorylation and neurotoxicity in an APOE-dependent manner. Our findings suggest a link between genetic risk factors for Alzheimer's disease with microglial lipid droplet accumulation and neurotoxic microglia-derived factors, potentially providing therapeutic strategies for Alzheimer's disease.

BRCA1-associated protein 1: Tumor predisposition syndrome and Kury-Isidor syndrome, from genotype-phenotype correlation to clinical management.

The BAP1 tumor suppressor gene encodes a deubiquitinase enzyme involved in several cellular activities, including DNA repair and apoptosis. Germline pathogenic variants in BAP1 have been associated with heritable conditions including BAP1 tumor predisposition syndrome 1 (BAP1-TPDS1) and a neurodevelopmental disorder known as Kury-Isidor syndrome (KURIS). Both these conditions are caused by monoallelic, dominant alterations of BAP1 but have never been reported in the same subject or family, suggesting a mutually exclusive genotype-phenotype correlation. This distinction is extremely important considering the early onset and aggressive nature of the types of cancer reported in individuals with TPDS1. Genetic counseling in subjects with germline BAP1 variants is fundamental to predicting the effect of the variant and the expected phenotype, assessing the potential risk of developing cancer for the tested subject and the family members who may carry the same variant and providing the multidisciplinary clinical team with the proper information to establish precise surveillance and management protocols.

Solitary CD8-Positive Primary Cutaneous Peripheral T-Cell Lymphoma: A Question of Classification.

ABSTRACT: Acral CD8(+) lymphoma is a provisional entity in the latest edition of the WHO Lymphoma Classification and is associated with a highly specific dot-like pattern of immunohistochemical expression of CD68. We report a case of an ulcerated solitary cutaneous lesion arising on the forehead of an adult man, which had a CD8(+) cytotoxic phenotype and areas of dot-like CD68 positivity, but with a number of features that significantly detracted from the classically described acral CD8(+) lymphoma. The nosological status of the lesion is discussed with respect to a preferred diagnosis of peripheral T-cell lymphoma, not otherwise specified.

Global Trend in Artificial Intelligence-Based Publications in Radiology From 2000 to 2018.

OBJECTIVE. The purpose of this study is to evaluate the global trend in artificial intelligence (AI)-based research productivity involving radiology and its subspecialty disciplines. CONCLUSION. The United States is the global leader in AI radiology publication productivity, accounting for almost half of total radiology AI output. Other countries have increased their productivity. Notably, China has increased its productivity exponentially to close to 20% of all AI publications. The top three most productive radiology subspecialties were neuroradiology, body and chest, and nuclear medicine.

Drug-induced dysphoria is enhanced following prolonged cocaine abstinence and dynamically tracked by nucleus accumbens neurons.

Negative reinforcement models postulate that addicts use drugs to alleviate negative affective states (e.g. dysphoria) associated with withdrawal. In a pre-clinical model, rats exhibit negative affect to a normally rewarding tastant when it predicts impending, but delayed cocaine, and nucleus accumbens (NAc) neurons dynamically track this state. Here, we examined the effects of short versus prolonged experimenter-imposed cocaine abstinence on negative affect, cocaine seeking and self-administration. Rats were given 14 saccharin-cocaine sessions; NAc activity and affective responses to the taste (i.e. taste reactivity) were measured during sessions 1 and 14. Next, following 1 or 30 days of abstinence, taste reactivity and cell firing were recorded in a three-phase test session: (1) intraoral saccharin infusions, (2) extinction and (3) cocaine self-administration. Results showed that 30 days of abstinence led to a significant enhancement of aversive responses to the cocaine-paired tastant, accompanied by a dramatic decline in NAc phasic activity during tastant infusion. While extinction behavior did not differ across groups, NAc phasic firing reemerged during drug seeking. Further, when drug was again readily available, greater aversion to the drug-paired tastant before and after abstinence was associated with increased self-administration following prolonged (30-day) abstinence in rats classified as high (not low) aversive. Collectively, these findings show that drug-induced dysphoria is enhanced following prolonged cocaine abstinence and that NAc neural signaling is dynamic, dampening when negative affect is at its highest (phase 1), but transitioning back 'online' during subsequent drug seeking and taking (phases 2 and 3).

Imaging of osteochondrosis.

Osteochondrosis is an abnormality of the epiphyses or epiphyseal equivalents (round bones and apophyses) during later stages of endochondral ossification. This process of abnormal endochondral ossification can occur at various locations throughout the body. The pathogenesis of osteochondrosis is under active investigation. In humans, the process of abnormal endochondral ossification has been attributed to a combination of vascular insult and trauma. Although the proposed etiology of osteochondrosis varies based on body part affected, the overall process is defined by necrosis, revascularization and repair. As such, common radiologic findings include those of osseous destruction and associated inflammation. The purpose of this review is to discuss the current understanding of osteochondroses as a disease entity and explore imaging features of osteochondroses throughout the body.

Registered nurses' perceptions and experiences of autonomy: a descriptive phenomenological study.

BACKGROUND: Professional autonomy is a key concept in understanding nurses' roles in delivering patient care. Recent research exploring the role of autonomy in the nursing work environment indicated that English and American nurses had differing perceptions of autonomy. This qualitative study aimed to explore the understanding and experiences of autonomy of nurses working in England. METHODS: A descriptive phenomenological analysis of data from 48 semi-structured interviews with registered nurses from two National Health Service (NHS) hospitals (purposive sample) was used to explore the concept of autonomy. RESULTS: Six themes were identified: working independently; working in a team; having professional skills and knowledge; involvement in autonomy; boundaries around autonomy; and developing autonomy requires support. A key finding was that nurses related autonomy to their clinical work and to the immediate work environment of their ward, rather than to a wider professional context. Nurses also perceived that autonomy could be turned off and on rather than comprising an integrated aspect of nursing. CONCLUSIONS: Findings suggest that nurses in England, as framed by the sample, had a local ward-focused view of autonomy in comparison to nurses in America, who were reported to relate autonomy to a wider involvement in hospital level committees. Findings further indicate that autonomy was practiced occasionally, rather than incorporated into practice. Findings highlight the need for nurses in England to adopt a broader perspective and actively contribute to writing hospital guidelines and policies that recognise the importance of autonomy to nurse training and practice.

Non-binary and binary transgender youth: Comparison of mental health, self-harm, suicidality, substance use and victimization experiences.

Background : Little research has compared the mental health and victimization experiences of non-binary youth depending on their sex assigned at birth (SAAB), or compared these two groups with binary transgender youth. Aims : To compare mental health, self-harm and suicidality, substance use and victimization experiences between non-binary and binary transgender young adults, both male assigned at birth (MAAB) and female assigned at birth (FAAB). Methods : Online survey data from 677 participants from the "Youth Chances" community study of 16 to 25 year olds in the United Kingdom was analyzed, comparing across binary participants (transgender females (n = 105) and transgender males (n = 210)) and non-binary participants (MAAB (n = 93) and FAAB (n = 269)). Results : Female SAAB participants (binary and non-binary) were more likely to report a current mental health condition and history of self-harm than male SAAB participants (binary and non-binary). Similarly, female SAAB participants (binary and non-binary) were more likely to report childhood sexual abuse than male SAAB participants (binary and non-binary); the reverse pattern was found for lifetime physical assault relating to being LGBTQ. Non-binary MAAB participants were less likely than the other groups to report past suicide attempts and previous help-seeking for depression/anxiety. Binary participants reported lower life satisfaction than non-binary participants. For all four groups, mental health problems, self-harm, suicidality, alcohol use and victimization experiences were generally higher than that of youth in general population studies. Conclusions : These findings highlight the importance of considering both non-binary versus binary gender identity and SAAB in relation to mental health problems, self-harm, suicidality and substance use in transgender youth. The roles of sexual abuse, other abuse and discrimination in contributing to increased rates of mental illness and self-harm in non-binary and binary transgender individuals, particularly those who were assigned female at birth, relative to those assigned male, require investigation.

Nucleus Accumbens Core and Shell Differentially Encode Reward-Associated Cues after Reinforcer Devaluation.

Nucleus accumbens (NAc) neurons encode features of stimulus learning and action selection associated with rewards. The NAc is necessary for using information about expected outcome values to guide behavior after reinforcer devaluation. Evidence suggests that core and shell subregions may play dissociable roles in guiding motivated behavior. Here, we recorded neural activity in the NAc core and shell during training and performance of a reinforcer devaluation task. Long-Evans male rats were trained that presses on a lever under an illuminated cue light delivered a flavored sucrose reward. On subsequent test days, each rat was given free access to one of two distinctly flavored foods to consume to satiation and were then immediately tested on the lever pressing task under extinction conditions. Rats decreased pressing on the test day when the reinforcer earned during training was the sated flavor (devalued) compared with the test day when the reinforcer was not the sated flavor (nondevalued), demonstrating evidence of outcome-selective devaluation. Cue-selective encoding during training by NAc core (but not shell) neurons reliably predicted subsequent behavioral performance; that is, the greater the percentage of neurons that responded to the cue, the better the rats suppressed responding after devaluation. In contrast, NAc shell (but not core) neurons significantly decreased cue-selective encoding in the devalued condition compared with the nondevalued condition. These data reveal that NAc core and shell neurons encode information differentially about outcome-specific cues after reinforcer devaluation that are related to behavioral performance and outcome value, respectively. SIGNIFICANCE STATEMENT: Many neuropsychiatric disorders are marked by impairments in behavioral flexibility. Although the nucleus accumbens (NAc) is required for behavioral flexibility, it is not known how NAc neurons encode this information. Here, we recorded NAc neurons during a training session in which rats learned that a cue predicted a specific reward and during a test session when that reward value was changed. Although encoding in the core during training predicted the ability of rats to change behavior after the reward value was altered, the NAc shell encoded information about the change in reward value during the test session. These findings suggest differential roles of the core and shell in behavioral flexibility.

The nursing work environment and quality of care: A cross-sectional study using the Essentials of Magnetism II Scale in England.

AIMS AND OBJECTIVES: To explore the structure of the Essentials of Magnetism II (EOMII) scale using data from nurses working in England; and to describe the impact of different aspects of the nursing work environment on nurse-assessed care quality (NACQ). BACKGROUND: The EOMII Scale was developed in the United States to measure nursing work environments. It has been widely used in the United States and in a number of other countries, but has not yet been used in the UK. DESIGN: Cross-sectional study. METHODS: Registered nurses (n = 247) providing direct patient care in two National Health Service hospitals in England completed the EOMII scale and a single-item measuring NACQ. Principal components analysis was used to assess the structure of the scale. Correlation and regression analyses were used to describe the relationships between factors and NACQ. RESULTS: A solution with explanatory variance of 45.25% was identified. Forty items loaded on five factors, with satisfactory consistency: (i) ward manager support; (ii) working as a team; (iii) concern for patients; (iv) organisational autonomy; and (v) constraints on nursing practice. While in univariate analyses, each of the factors was significantly associated with NACQ, in multivariate analyses, the relationship between organisational autonomy and NACQ no longer reached significance. However, a multiple mediation model indicated that the effect of organisational autonomy on NACQ was mediated by nurse manager support, working as a team and concern for patients but not constraints on nursing practice. CONCLUSIONS: Subscales of the EOMII identified in an English sample of nurses measured important aspects of the nursing work environment, each of which is related to NACQ. RELEVANCE TO CLINICAL PRACTICE: The EOMII could be a very useful tool for measuring aspects of the nursing work environment in the English Trusts particularly in relation to the quality of care.

Preoperative vaginal estrogen and midurethral sling exposure: a retrospective cohort study.

INTRODUCTION AND HYPOTHESIS: We evaluated whether the use of estrogen vaginally prior to synthetic midurethral sling insertion mediates the risk of mesh exposure. A secondary aim was to evaluate other factors that may be associated with mesh exposure. METHODS: We performed a retrospective cohort study of patients undergoing midurethral sling insertion from January to December 2010 within the Southern California Permanente Medical Group. Women who used estrogen vaginally prior to surgery were classified as those who filled a prescription between 1 and 45 days before surgery or whose medical records indicated its use at the time of preoperative evaluation. Logistic regression analysis was used to calculate odds ratios (OR) and 95 % confidence intervals (CI) for factors associated with mesh exposure while controlling for confounding variables. RESULTS: A total of 1544 patients met inclusion criteria, of whom 248 (16.1 %) used estrogen vaginally prior to surgery. Mean age was 53.7 years (range 27-89). Thirty-seven (2.4 %) women were diagnosed with mesh exposure, of whom 19 underwent surgical reoperation. In multivariate logistic regression analysis, preoperative use of estrogen vaginally was not associated with the risk of mesh exposure (OR 0.79, CI 0.26-2.38, p = 0.67). Age, body mass index, menopausal status, use of hormone replacement therapy, smoking status, and diabetes were not associated with risk of mesh exposure. CONCLUSIONS: Preoperative use of estrogen vaginally did not appear to mediate the risk of mesh exposure following midurethral sling placement in this cohort.

Health Partners of Western Ohio: Integrated Care Case Study.

Health centers are unique health care delivery organizations in which multiple disciplines, such as primary care, dental, behavioral health, pharmacy, podiatry, optometry and alternative medicine, are often located at the same site. Because of this characteristic, many health centers have developed systems of integrated care. This paper describes the characteristics of health centers and highlights the integrated health care delivery system of one early adopter health center, Health Partners of Western Ohio.

Reciprocal associations between smoking cessation and depression in older smokers: findings from the English Longitudinal Study of Ageing.

BACKGROUND: Depression is a particular problem in older people and it is important to know how it affects and is affected by smoking cessation. AIMS: To identify reciprocal, longitudinal relationships between smoking cessation and depression among older smokers. METHOD: Across four waves, covering six years (2002-2008), changes in smoking status and depression, measured using the 8-item Centre for Epidemiologic Studies Depression Scale, were assessed among recent ex-smokers and smokers (n = 2375) in the English Longitudinal Study of Ageing. RESULTS: In latent growth curve analysis, smoking at baseline predicted depression caseness longitudinally and vice versa. When both processes were modelled concurrently, depression predicted continued smoking longitudinally (B(ß) = 0.21 (0.27); 95% CI = 0.08-0.35) but not the other way round. This was the case irrespective of mental health history and adjusting for a range of covariates. CONCLUSIONS: In older smokers, depression appears to act as an important barrier to quitting, although quitting has no long-term impact on depression.

Prelimbic and infralimbic cortical regions differentially encode cocaine-associated stimuli and cocaine-seeking before and following abstinence.

Cocaine stimuli often trigger relapse of drug-taking, even following periods of prolonged abstinence. Here, electrophysiological recordings were made in rats (n = 29) to determine how neurons in the prelimbic (PrL) or infralimbic (IL) regions of the medial prefrontal cortex (mPFC) encode cocaine-associated stimuli and cocaine-seeking, and whether this processing is differentially altered after 1 month of cocaine abstinence. After self-administration training, neurons (n = 308) in the mPFC were recorded during a single test session conducted either the next day or 1 month later. Test sessions consisted of three phases during which (i) the tone-houselight stimulus previously paired with cocaine infusion during self-administration was randomly presented by the experimenter, (ii) rats responded on the lever previously associated with cocaine during extinction and (iii) the tone-houselight was presented randomly between cocaine-reinforced responding during resumption of cocaine self-administration. PrL neurons showed enhanced encoding of the cocaine stimulus and drug-seeking behavior (under extinction and self-administration) following 30 days of abstinence. In contrast, although IL neurons encoded cocaine cues and cocaine-seeking, there were no pronounced changes in IL responsiveness following 30 days of abstinence. Importantly, cue-related changes do not represent a generalised stimulus-evoked discharge as PrL and IL neurons in control animals (n = 4) exhibited negligible recruitment by the tone-houselight stimulus. The results support the view that, following abstinence, neural encoding in the PrL but not IL may play a key role in enhanced cocaine-seeking, particularly following re-exposure to cocaine-associated cues.

It takes patience and persistence to get negative feedback about patients' experiences: a secondary analysis of national inpatient survey data.

BACKGROUND: Patient experience surveys are increasingly used to gain information about the quality of healthcare. This paper investigates whether patients who respond before and after reminders to a large national survey of inpatient experience differ in systematic ways in how they evaluate the care they received. METHODS: The English national inpatient survey of 2009 obtained data from just under 70,000 patients. We used ordinal logistic regression to analyse their evaluations of the quality of their care in relation to whether or not they had received a reminder before they responded. RESULTS: 33% of patients responded after the first questionnaire, a further 9% after the first reminder, and a further 10% after the second reminder. Evaluations were less positive among people who responded only after a reminder and lower still among those who needed a second reminder. CONCLUSIONS: Quality improvement efforts depend on having accurate data and negative evaluations of care received in healthcare settings are particularly valuable. This study shows that there is a relationship between the time taken to respond and patients' evaluations of the care they received, with early responders being more likely to give positive evaluations. This suggests that bias towards positive evaluations could be introduced if the time allowed for patients to respond is truncated or if reminders are omitted.

Prevention of NICU Admission Hypothermia in Moderate- and Late-Preterm Infants.

BACKGROUND: Neonatal hypothermia is a common and preventable cause of neonatal morbidity and mortality. Although hypothermia prevention has been extensively studied in infants <32 weeks' gestation, the authors of few studies have targeted moderate- and late-preterm infants (MLPIs) in the delivery room. METHODS: This quality improvement initiative was conducted from June 2019 to June 2023 at the Massachusetts General Hospital NICU and Labor and Delivery Unit. All inborn MLPIs 32 + 0/7 to 36 + 6/7 weeks' gestation admitted to the NICU were included. We expanded thermoregulatory measures typically used in protocols for infants <32 weeks' gestation, including increasing delivery room ambient temperature to 74°F and thermal mattress use. The primary outcome was hypothermia (<36.5°C) after NICU admission. The balancing measure was hyperthermia (≥38 °C). RESULTS: During the study period, there were 566 inborn MLPIs with a mean gestational age of 34 + 3/7 weeks and a mean birth weight of 2269 g. Special cause variation in neonatal hypothermia incidence was observed with a decrease from a mean baseline of 27% to 7.8% postintervention. Special cause variation was observed in hyperthermia incidence, with an increase from 1.4% to 6.2% postintervention largely initially associated with noncompliance with the protocol for thermal mattress removal. CONCLUSIONS: The expansion of several thermoregulation techniques commonly used in infants <32 weeks' gestation, particularly thermal mattress use, was associated with a decreased incidence of NICU admission hypothermia in MLPIs, with an increase in mild hyperthermia predominantly associated with concomitant polyethylene wrap use.

The genetic susceptibility in the development of malignant pleural mesothelioma: somatic and germline variants, clinicopathological features and implication in practical medical/surgical care: a narrative review.

Background and Objective: Malignant pleural mesothelioma (MPM) is a very aggressive primary tumor of the pleura whose main risk factor is exposure to asbestos. However, only a minority of exposed people develops MPM and the incidence of MPM cases without an apparent association with asbestos exposure has been increasing in recent years, suggesting that genetic predisposing factors may play a crucial role. In addition, several studies reported familial cases of MPM, suggesting that heredity may be an important and underestimated feature in MPM development. Several candidate genes have been associated with a predisposition to MPM and most of them play a role in DNA repair mechanisms: overall, approximately 20% of MPM cases may be related to genetic predisposition. A particular category of patients with high susceptibility to MPM is represented by carriers of pathogenic variants in the BAP1 gene. Germline variants in BAP1 predispose to the development of MPM following an autosomal dominant pattern of inheritance in the familial cases. MPMs in these patients are significantly less aggressive, and patients require a multidisciplinary approach that involves genetic counseling, medical genetics, pathology, surgical, medical, and radiation oncology expertise. In the present narrative review, we presented a comprehensive overview of genetic susceptibility in the development of MPM. Methods: The narrative review is based on a selective literature carried out in PubMed in 2023. Inclusion criteria were original articles in English language, and clinical trials (randomized, prospective, or retrospective). Key Content and Findings: We summarized the somatic and germline variants and the differences in terms of clinicopathological features and prognosis between gene-related MPM (GR-MPM) and asbestos-related MPM (AR-MPM). We also discussed the indications for screening, genetic testing, and surveillance of patients with BAP1 germline variants. Conclusions: In this narrative review, we have emphasized that the BAP1 gene's harmful germline variations are inherited in an autosomal dominant manner in familial cases. MPMs in individuals with these variations are less severe, and their medical care necessitates a collaborative effort. Additionally, we have outlined the current therapeutic prospects for MPM, including the possibility of gene-specific therapy, which is currently promising but still requires clinical validation.

Superior colliculus mediates cervical dystonia evoked by inhibition of the substantia nigra pars reticulata.

Cervical dystonia (CD; spasmodic torticollis) can be evoked by inhibition of substantia nigra pars reticulata (SNpr) in the nonhuman primate (Burbaud et al., 1998; Dybdal et al., 2012). Suppression of GABAergic neurons that project from SNpr results in the disinhibition of the targets to which these neurons project. It therefore should be possible to prevent CD by inhibition of the appropriate nigral target region(s). Here we tested the hypothesis that the deep and intermediate layers of the superior colliculus (DLSC), a key target of nigral projections, are required for the emergence of CD. To test this hypothesis, we pretreated the DLSC of four macaques with the GABA(A) agonist muscimol to determine whether this treatment would prevent CD evoked by muscimol infusions in SNpr. Our data supported this hypothesis: inhibition of DLSC attenuated CD evoked by muscimol in SNpr in all four animals. In two of the four subjects, quadrupedal rotations were evoked by muscimol application into SNpr sites that were distinct from those that induced dystonia. We found that inhibition of DLSC did not significantly alter quadrupedal rotations, suggesting that this response is dissociable from the SNpr-evoked CD. Our results are the first to demonstrate a role of DLSC in mediating the expression of CD. Furthermore, these data reveal a functional relationship between SNpr and DLSC in regulating posture and movement in the nonhuman primate, raising the possibility that the nigrotectal pathway has potential as a target for therapeutic interventions for CD.