Search

• What is the primary question addressed by this study? What is the prevalence of Alzheimer disease and related dementias (ADRD) among Veterans hospitalized for heart failure that also have insomnia, depression, or comorbid insomnia and depression? • What is the main finding of this study? Comorbid insomnia and depression are associated with the highest prevalence of ADRD at 34 per 100 persons. This is significantly higher than persons with either insomnia (21 per 100) or depression (24 per 100). • What is the meaning of the finding? Persons with comorbid insomnia and depression are at a highest risk of ADRD, and it is clinically important to screen for both insomnia and depression in persons hospitalized for heart failure as this may lead to earlier ADRD detection. To examine prevalence of Alzheimer Disease and related dementias (ADRD) and patient characteristics as a function of comorbid insomnia and/or depression among heart failure (HF) patients discharged from hospitals. Retrospective cohort descriptive epidemiology study. VA Hospitals. N = 373,897 Veterans hospitalized with heart failure from October 1, 2011 until September 30, 2020. We examined VA and Center for Medicare & Medicaid Services (CMS) coding in the year prior to admission using published ICD-9/10 codes for dementia, insomnia, and depression. The primary outcome was the prevalence of ADRD and the secondary outcomes were 30-day and 365-day mortality. The cohort were predominantly older adults (mean age = 72 years, SD = 11), male (97%), and White (73%). Dementia prevalence in participants without insomnia or depression was 12%. In those with both insomnia and depression, dementia prevalence was 34%. For insomnia alone and depression alone, dementia prevalence was 21% and 24%, respectively. Mortality followed a similar pattern with highest 30-day and 365-day mortality higher in those with both insomnia and depression. These results suggest that persons with both insomnia and depression are at an increased risk of ADRD and mortality compared to persons with one or neither condition. Screening for both insomnia and depression, especially in patients with other ADRD risk factors, could lead to earlier identification of ADRD. Understanding comorbid conditions which may represent earlier signs of ADRD may be critical in the identification of ADRD risk. [ABSTRACT FROM AUTHOR]

There has been much debate regarding the aetiology and pathogenesis of hallux valgus and it appears to be multifactorial with contracture or tightness of the Achilles tendon and more specifically the gastrocnemius being implicated as an intrinsic factor. The purpose of this study was to look at the association of gastrocnemius tightness, genu valgum and hallux valgus. A prospective case-control study with 25 patients in each group was carried out over a 12-month period. The case group observed adult patients who were referred primarily because of symptomatic hallux valgus and were assessed for the following: hallux valgus stage; presence or absence of isolated gastrocnemius tightness; presence or absence of genu valgum. The control group excluded those with pre-existing hallux valgus, genu valgum and rheumatoid arthritis and were assessed for isolated gastrocnemius tightness. There was a statistically significant association between the presence of genu valgum and hallux valgus when comparing both groups with a p <.001. There was also a statistically significant association between the Silfverskiöld test and the presence of hallux valgus, as well as the Silfverskiöld test and the presence of genu valgum with a p <.001. This study is the first to describe the association of gastrocnemius tightness, genu valgum and hallux valgus. Further studies are required to assess this relationship but knowledge and awareness of it can be applied by clinicians when considering the most appropriate management options with patients. [ABSTRACT FROM AUTHOR]

Pretibial panniculitis ossificans is a rare condition. In this report, we describe a 67-year-old male localized to his right pretibial tissue, approximately 20 years after contusion to the same area. [ABSTRACT FROM AUTHOR]

Objective: Hamate hook fractures are rare injuries, comprising 2% to 4% of all carpal fractures. Climbing athletes seem to be affected more frequently than others, as they strain the passive and active anatomical structures of their hands and fingers to maximum capacity during training or competing. This stress is transmitted to the hook of the hamate by tightened flexor tendons, which creates high contact pressure to the ulnar margin of the carpal tunnel. Injuries of the hamate hook, caused by contact pressure of the anatomical structures, are rare and occur nearly exclusively during climbing.Methods: We diagnosed 12 athletes with hamate hook fractures who presented with diffuse pain in the wrist joint, which occurred either during or after climbing. Radiographs or computed tomography revealed fractures in the hamate bones in most of the patients; therapy consisted of consequent stress reduction.Results: Follow-up investigations found that all athletes were free of symptoms after 10.7 ± 5.1 (6-24) (mean ± standard deviation with range) weeks. Resection of the hamate hook was necessary in 3 patients. All patients regained their preinjury climbing level.Conclusion: Climbers with an unspecific, diffuse pain in the wrist need to be examined by radiograph and, if radiograph is unclear, computed tomography or magnetic resonance imaging to detect or exclude the diagnosis of hamate fracture in order to avoid severe complications. [ABSTRACT FROM AUTHOR]

Healthcare workers in long-term care settings and group homes for the disabled are at signi?cant risk of contracting COVID-19 and subsequently infecting the residents, fellow co-workers, and their family. In addition, lower paying long-term care healthcare workers maybe working multiple jobs which increases the risk of exposure. In April 2020, 27% of all deaths in the population was among residents in long-term care. The elderly population has the greatest risk for mortality from COVID-19 (Liu et al. 2020) and are disproportionality a?ected by social distance and self-isolation. Most long-term care settings have implemented lockdowns preventing families from visiting and limiting interactions among residents. Social isolation of the elderly is considered a serious public health concern. Social disconnection is a risk factor for increased depression and anxiety among the elderly. It is hypothesized that elderly persons are at high risk for poor mental health outcomes from the COVID-19 pandemic. The Alzheimer's Disease International suggest that those with dementia "may become more anxious, angry, stressed, agitated, and withdrawn during the outbreak". These factors potentially may increase stress on healthcare workers in long-term care settings beyond the fears of exposure and transmitting COVID-19 to their families. There are few studies to date that examine the mental health impact of COVID-19 on healthcare workers in long-term care. The United Nations has highlighted the mental health risk to workers in long-term care. "First responders and front line workers, particularly workers in health and long-term care play a crucial role in ?ghting the outbreak and saving lives. However, they are under exceptional stress, being faced with extreme workloads, di?cult decisions, risks of becoming infected and spreading infection to families and communities, and witnessing deaths of patients." Healthcare workers in long-term care facilities, and assisted living facilities in Rhode Island were given questionnaires to complete that examined mental health and risk factors associated with COVID-19. The questionnaire includes items on the healthcare worker's experience with COVID-19. Resilience is measured using The Brief Resilience Scale assessing the individual's ability to bounce back or recover from stress. Subjective incompetence is de?ned as the perceived incapacity to perform tasks and express feelings deemed appropriate in a stressful situation. Increasing distress and subjective incompetence may convert a normal reaction to stress into mental disorder requiring intervention. Demoralization is measured using the Demoralization Scale-II. Depression and anxiety is measured using two of the most commonly used screens in clinical care, the PHQ-9 for depression and the GAD-7 for generalized anxiety. Family functioning during and before the COVID-19 pandemic is measured using the three-item Brief Assessment of Family Functioning. Social support is measured during and before the COVID-19 pandemic using the emotional-informational support subscale of the Brief Social Support Scale derived from the Medical Outcomes Study Social Support Survey. Coronavirus Anxiety Scale is a mental health screener designed to aid in the identi?cation of probable cases of dysfunctional anxiety associated with the COVID-19 pandemic. The fear of Coronavirus-19 Scale was used to measure this construct. The ?ve-item Primary Care PTSD Screen was adapted to COVID-19 as a traumatic event. Items measuring healthcare worker workplace stress was developed based on a items from a number of existing scales. A 15-item health care workers attitudes toward the management of COVID-19 in the long-term care facility was developed by the research team that focuses on training of sta?, safety, and resident care. Preliminary data will be presented. Data collection is currently underway. There are 65 assisted living facilities and 85 nursing homes in Rhode Island. Approximately 10% of the facilities are currently participating with the aim to recruit nearly all facilities in the state. The hypotheses to be tested is that healthcare workers in long-term care settings have mental health issues including demoralization, depression and anxiety due to the COVID-19 pandemic disaster. That those who are in facilities with COVID-19 residents have increased stress. Those facilities that have placed increased demands on healthcare workers will have employees that are having more difficulty in dealing with the COVID-19 pandemic. This study examines how healthcare workers in long-term care facilities have coped during the COVID-19 pandemic and the impact on their mental health; factors that protect or place the healthcare worker at risk for poorer mental health outcomes (depression, anxiety, demoralization, post-traumatic stress); and factors during COVID-19 that place the healthcare worker for poorer mental health outcomes during COVID-19 pandemic. Department of Psychiatry of Psychiatry and Human Behavior, Warren Alpert Medical School of Brown University, Lifespan [ABSTRACT FROM AUTHOR]

• Use of non-absorbable sutures in Achilles Tendon rupture repair is associated with higher rates of postoperative infections. • Neither braided or monofilament sutures were associated with higher rates of infections post TA rupture repair. • Type of suture material was not associated with re-rupture rates following Achilles tendon rupture repair. The impact of suture type on tensile strength, re-rupture rates and infection risk in Achilles tendon rupture repair is not been well established. The aim of this review is to evaluate existing literature on the associated risk of postoperative infection with absorbable and non-absorbable suture materials in Achilles tendon rupture repair. A systematic review of search databases PubMed; Google Scholar; and OVID Medline was made to identify studies related to complications associated with Achilles tendon rupture repair. PRISMA guidelines were utilised for this review. Meta-analysis was used to compare rupture rates and infections following rupture repair. 12 studies with a total of 460 patients, 230 in both nonabsorbable and absorbable suture groups were included for analysis. Risk of wound complications was significantly higher in patients with non-absorbable sutures (p < 0.001). Nonabsorbable braided sutures is associated with the highest risk of postoperative wound complications following Achilles tendon rupture repair. [ABSTRACT FROM AUTHOR]

Summary: Background: Sport climbers strain the passive and active anatomical structures of their hands and fingers to their maximum when training as well as in competitions. Materials and Methods: For 17 high level climbers with diffuse pain in the hand and wrist joint, we ran MRI with standard sequences. Results: In 12 patients the MRI revealed osseous edema due to overload at the respective area of interest, mainly in the distal radius, the distal ulna or the carpal bones, which could not be identified as other diagnoses such as inflammations, tumors or injuries. We classified those edema as due to overload. Conclusions: The edema resulted as a stress reaction to highly intensive training and climbing, with presumably high traction to the wrist area. The therapy of choice consisted of consequent stress reduction and a break from sporty activity. The control MRIs demonstrated that even with a consequent stress reduction these edema need 3 to 4 months to disappear completely. Climbers with diffuse pain in wrist and fingers should be examined with MRI and the posing of the question of a bone edema. Level of Evidence: “Case series” mit Evidenzlevel III-IV. [Copyright &y& Elsevier]

Abstract: Aims: In the present review we summarize current knowledge on the concept of intraneuronal Aβ as a determinant for neuron loss and other pathological alterations in transgenic models for Alzheimer disease. Main methods: We discuss the use of transgenic mouse and non-vertebrate transgenic models accumulating intracellular Aβ peptides and their impact on the ongoing discussion. Key findings: Intraneuronal Aβ accumulation in transgenic models is intimately linked to pathological alterations including neuron loss. One of the technical caveats for visualizing intraneuronal Aβ is the antibody used to unequivocally demonstrate its presence. Very often antibodies were used that recognize both Aβ and APP, leading to false positive results due to misinterpretation. Significance: Whereas a clear relationship between intraneuronal Aβ accumulation and neuron loss is evident in transgenic mouse models it remains an unresolved issue whether the concept of intraneuronal Aβ can be integrated into the human pathology as well. [Copyright &y& Elsevier]

Purpose: To study the configuration of the proximal interphalangeal joint volar plate (VP) in the crimp grip position (metacarpophalangeal joint at 0° to 45° flexion, proximal interphalangeal joint at 90° to 100° flexion, and distal interphalangeal joint at 0° to 10° hyperextension) using magnetic resonance imaging techniques in healthy volunteers and cadaver fingers and to compare the results with histological sections. Methods: Magnetic resonance imaging was performed on 24 fingers of 8 healthy volunteers and 12 fingers of 4 embalmed cadaver hands in the neutral position and in the crimp grip position. The translation of the VP body relative to the middle phalanx base during finger flexion was measured. In 6 of 12 cadaver specimens, a load of 10 N was applied to the flexor tendons to examine how this would affect the histological VP fiber configuration. Results: When the flexor tendons were under load in the crimp grip position, the volunteers'' VP body was translated an average of 3.2 mm, and the cadaver fingers'' VP body was translated an average of 3.0 mm, relative to the middle phalanx base in a distal direction. Histological analysis of the crimp grip position revealed reversing fibers in the VP insertion at the base of the middle phalanx when the flexor tendons were under load and the VP body was translated. When no load was applied in the crimp grip position, no translation of the VP body occurred. Conclusions: This article describes a VP translation in a distal direction relative to the middle phalanx base in the crimp grip position when the flexor tendons are under load. Clinical relevance: A more precise knowledge of the histological properties of the proximal interphalangeal joint VP during finger flexion can be expected to provide greater diagnostic capabilities and can lead to a better comprehension of injuries. [Copyright &y& Elsevier]

Abstract: When it comes to creativity, intuitive methods like brain storming or mind mapping are most likely to be named. These techniques aim at developing many problem solving ideas by supporting the ability to build associations. The contrary concept which searches for only one optimal resolution has gone virtually unnoticed so far. Methods approaching their subject from this angle rely on a combined collection of standardised matrices. They are similar to brainstorming and mind mapping which help to generate innovation, although they differ from these in their target objective. This paper aims at presenting the characteristics of the progressive methods by comparing rhetorical topics with TRIZ. [Copyright &y& Elsevier]

Abstract: Loss of cholinergic neurons in the Nucleus Basalis of Meynert in Alzheimer''s disease (AD) patients was one of the first discoveries of neuron loss in AD. Despite an intense focus on the cholinergic system in AD, the reason for this cholinergic neuron loss is yet unknown. In the present study we examined Aβ-induced pathology and neuron loss in the cholinergic system of the bigenic APP/PS1KI mouse model. Expression of the APP transgene was found in ChAT-positive neurons of motor nuclei accompanied by robust intracellular Aβ accumulation, whereas no APP expressing neurons and thus no intracellular Aβ accumulation were found in neither the forebrain or pons complexes, nor in the caudate putamen. This expression pattern was used as a model system to study the effect of intra- and extracellular Aβ accumulation on neuron loss in the cholinergic system. Stereological quantification revealed a loss of ChAT-positive neurons in APP/PS1KI mice only in the motor nuclei Mo5 and 7N accumulating intracellular Aβ. This study supports the hypothesis of intracellular Aβ accumulation as an early pathological alteration contributing to cell death in AD. [Copyright &y& Elsevier]

Abstract: The staining protocols so far applied to study intracellular Aβ accumulation in human tissue have been inconsistent with varying use of heat and formic acid (FA) for antigen retrieval. Microwave heat treatment has been reported to enhance the staining of intraneuronal Aβ as compared to no or enzymatic pretreatment. FA is widely used to increase the staining of plaque pathology in AD, yet the effect of FA on intraneuronal Aβ staining has been reported to be low and similar to the effect of heat or even to counteract the enhancing effect of heat pretreatment on intraneuronal Aβ immunohistochemical detection. To overcome these inconsistencies, there is a need for optimization of the staining protocol for intraneuronal Aβ detection and more knowledge is required concerning the effects of the different antigen retrieval methods. In the present work, we optimized the staining protocol for intraneuronal Aβ in paraffin-embedded sections in relation to heat and FA using four different mouse models known to accumulate intraneuronal Aβ peptides. It was found that FA is essential for the staining of highly aggregated intraneuronal Aβ peptides in AD transgenic mouse tissue. [Copyright &y& Elsevier]

Abstract: Loss of neurons in the hippocampus and other brain regions is, besides the occurrence of plaques and tangles, a neuropathological feature of Alzheimer''s disease (AD). In recent years a plethora of transgenic mouse models overexpressing mutant amyloid precursor protein (APP) has been developed, which represent valuable research tools. Whereas extracellular plaque pathology is a common feature of these models, neuronal loss is a rather rare characteristic. In the present study, we quantified the number of neurons in the dentate gyrus granule layer (GCL) in 2- and 12-month-old APP/PS1KI mice, a mouse model that has been previously shown to have significant loss of neurons in the CA1 layer of the hippocampus. Stereological analysis revealed a strongly significant decrease of GCLs in aged APP/PS1KI mice, compared to age-matched PS1KI control animals (−44%), however, the volume of the GCL was not different. [Copyright &y& Elsevier]

Applying the orders of outcome framework introduced by Olsen et al. (Crafting Coastal Governance in a Changing World, The Coastal Resources Center, Narragansett, 2003, 376pp.), this article describes how the Tanzania Coastal Management Partnership (TCMP) built the enabling conditions necessary to establish a national integrated coastal management (ICM) program in Tanzania. The article shows how the TCMP created a nested governance system that features partnering with national and district government agencies, local ICM programs, scientists and non-governmental organizations (NGOs). The article introduces the regional East African context and local Tanzanian context for coastal management—contexts that have provided strong roots for ICM in Tanzania, and a body of experience on which to construct a national ICM program. The article outlines the key management strategies used by the TCMP to create enabling conditions for a national ICM program, describes how the national ICM Strategy was approved, and finally presents the key outcomes seen by the Partnership by early 2004. [Copyright &y& Elsevier]

The objective of this study was to investigate spectral Doppler ultrasound (US) for monitoring extracorporeal shock-wave lithotripsy (ESWL). In vitro experiments with model stones showed that Doppler spectra acquired after a shock wave hit result in a high peak followed by a decaying signal. The duration of decay was dependent on shock-wave energy, stone size, gas content of the water and the level of disintegration. It typically ranged from 30 ms to 150 ms. It was found, by comparison with optical high-speed imaging and US B-scan imaging, that the signal originated from fragments released by the stone and cavitation. If the monitored volume contained no target, the signal duration was significantly shorter. By this means, hits were reliably distinguished from misses. The results of clinical treatments were highly consistent with those of in vitro experiments. Therefore, spectral Doppler US is an excellent tool for hit/miss monitoring in ESWL. (E-mail: cbohris@dornier.com) [Copyright &y& Elsevier]

α-Synuclein is a presynaptic protein that is implicated in the pathogenesis of various neurodegenerative diseases. Missense mutations in the α-synuclein gene are linked to familial cases of Parkinson''s disease (PD), and it has further been shown that α-synuclein is a major constituent of the Lewy bodies in sporadic PD and dementia with Lewy body (DLB). The contribution of α-synuclein to the pathological changes in Alzheimer''s disease (AD) has been currently a matter of scientific debate. Some reports hypothesized that α-synuclein may play a role in amyloid β/A4 protein (Aβ) aggregation in senile plaques, whereas recent reports challenged this finding by showing a lack of α-synuclein-immunoreactivity in Aβ plaques. In this review, we report on recent findings on the physiological and pathological role of α-synuclein and try to elucidate its possible contribution to AD pathology. [Copyright &y& Elsevier]

The weekend warrior has long been prey to musculoskeletal injuries as a result of intermittent, high intensity activity. The Achilles tendon is known to be particularly vulnerable in this population cohort but during the COVID-19 lockdowns in Ireland and all over the world there has been a certain level of detraining and deconditioning among all age groups and populations. Throughout the worldwide restrictions, viral internet challenges and dances have encapsulated the spirit of a global community with the 'Jerusalema' dance being no exception. The rise of this particular viral sensation was at the detriment of the Achilles tendons of three middle aged gentlemen on who we base our case series. Over the space of ten days three cases of Achilles tendon rupture repair presented to the emergency department in Midlands Regional Hospital Tullamore (MRHT) with the mechanism of tendon rupture being through the 'Jerusalema' dance. These patients were surgically managed in line with local institution practice and postoperative outcomes were good with no complications noted. Follow up is ongoing. This retrospective case series is based on the impact of the 'Jerusalema Dance' on presentations of Achilles tendon rupture to the Emergency Department in a single regional hospital from January to March 2021. We used these cases in conjunction with a review of current literature to highlight the benefit of an integrated Achilles Tendon rehabilitation programme in this at-risk patient cohort. This paper highlights the dangers inherent when well intentioned, but physically deconditioned individuals endeavour to perform a physical exercise which is deceptively demanding. Going forward, viral challenges such as the 'Jerusalema' may contribute to new and interesting mechanisms of injuries in our 'weekend warrior' cohort. In addition to this, given the global deconditioning seen due to the COVID 19 pandemic and subsequent lockdowns we may see a higher rate of Achilles tendon injuries in the near future across a multitude of patient cohorts. Level one evidence suggests that conservative treatment is just as effective as surgical treatments in the majority of patients with an Achilles tendon rupture, as long as a protocol of rehabilitation with early weightbearing is performed. Our accelerated rehabilitation programme in MRHT is in line with others however internal audit and new literature in the future may enable us to refine it further. • Achilles Tendon Rupture is common amongst the conditioned and deconditioned population. • Surgical and conservative management options are widely explored in the literature. • Viral dance challenges such as the Jerusalema offer new and interesting patterns of injury. • An early weightbearing rehabilitation programme after TA rupture shows lower re-rupture rates. [ABSTRACT FROM AUTHOR]

Examine physical function change and physical therapy (PT) use in short-stay and long-stay residents not infected by CoVID-19 within Veterans Affairs (VA) Community Living Centers (CLCs). Retrospective cohort study using Minimum Data Set (MDS) 3.0 assessments. 12,606 Veterans in 133 VA CLCs between September 2019 and September 2020. Difference in physical function [MDS Activities of Daily Living Score (MDS-ADL)] and PT use (minutes in past 7 days) from admission to last assessment in a period were compared between the pre-CoVID-19 (September 2019 to February 2020) and early CoVID-19 (April 2020 to September 2020) period using mixed effects regression with multivariable adjustment. Assessments after a positive CoVID-19 test were excluded. Differences were examined in the sample and repeated after stratifying into short- and long-stay stratums. Veterans admitted during early CoVID-19 had more comorbidities, worse MDS-ADL scores, and were more often long-stay residents compared with those admitted during pre-CoVID-19. In comparison to pre-CoVID-19, Veterans in VA CLCs during early CoVID-19 experienced greater improvements in their MDS-ADL (−0.49 points, 95% CI –0.27, −0.71) and received similar minutes of therapy (2.6 minutes, 95% CI –0.8, 6.0). Stratification revealed short-stay residents had relative improvements in their function (−0.69 points, 95% CI –0.44, −0.94) and higher minutes of PT (5.1 minutes, 95% CI 0.9, 9.2) during early CoVID-19 whereas long-stay residents did not see differences in functional change (0.08 points, 95% CI –0.36, 0.51) or PT use (−0.6 minutes, 95% CI –6.1, 4.9). During early CoVID-19, physical function improved while the amount of PT received was maintained compared with pre-CoVID-19 for Veterans in VA CLCs. Short-stay residents experienced greater improvements in physical function and increases in PT use. These findings may be partly due to selection bias relating to Veterans admitted to CLCs during early CoVID-19. [ABSTRACT FROM AUTHOR]

Wandering behavior in nursing home (NH) residents could increase risk of infection. The objective of this study was to assess the association of wandering behavior with SARS-CoV-2 infection in Veterans Affairs (VA) Community Living Center (CLC) residents. Retrospective cohort study. Veterans residing in 133 VA CLCs. We included residents with SARS-CoV-2 test from March 1, 2020 to December 31, 2020 from VA electronic medical records. We identified CLC residents with wandering on Minimum Data Set 3.0 assessments and compared them with residents without wandering. The outcome was SARS-CoV-2 infection, as tested for surveillance testing, in those with and without wandering. Generalized linear model with Poisson link adjusted for relevant covariates was used. Residents (n = 9995) were included in the analytic cohort mean, (SD) age 73.4 (10.7); 388 (3.9%) women. The mean (SD) activities of daily living score in the overall cohort was 13.6 (8.25). Wandering was noted in 379 (3.8%) (n = 379) of the cohort. The exposure groups differed in prior dementia (92.6% vs 62.1%, standardized mean difference [SMD] = 0.8) and psychoses (41.4% vs 28.1%, SMD = 0.3). Overall, 12.5% (n = 1248) tested positive for SARS-CoV-2 and more residents among the wandering group were SARS-CoV-2 positive as compared with those in the group without wandering (19% [n = 72] vs 12.2% [n = 1176], SMD = 0.19). Adjusting for covariates, residents with wandering had 34% higher relative risk for SARS-CoV-2 infection (adjusted relative risk, 1.34; 95% CI, 1.04–1.69). CLC residents with wandering had a higher risk of SARS-CoV-2 infection. This may inform implementation of infection control and isolation policies as NHs attempt to balance ethical concepts of resident autonomy, proportionality, equity, and utilitarianism. [ABSTRACT FROM AUTHOR]

Medical comorbidity, particularly cardiovascular diseases, contributes to high rates of hospital admission and early mortality in people with schizophrenia. The 30 days following hospital discharge represents a critical period for mitigating adverse outcomes. This study examined the odds of successful community discharge among Veterans with schizophrenia compared to those with major affective disorders and those without serious mental illness (SMI) after a heart failure hospital admission. Data for Veterans hospitalized for heart failure were obtained from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. Psychiatric diagnoses and medical comorbidities were assessed in the year prior to hospitalization. Successful community discharge was defined as remaining in the community without hospital readmission, death, or hospice for 30 days after hospital discharge. Logistic regression analyses adjusting for relevant factors were used to examine whether individuals with a schizophrenia diagnosis showed lower odds of successful community discharge versus both comparison groups. Out of 309,750 total Veterans in the sample, 7377 (2.4%) had schizophrenia or schizoaffective disorder and 32,472 (10.5%) had major affective disorders (bipolar disorder or recurrent major depressive disorder). Results from adjusted logistic regression analyses demonstrated significantly lower odds of successful community discharge for Veterans with schizophrenia compared to the non-SMI (Odds Ratio [OR]: 0.63; 95% Confidence Interval [CI]: 0.60, 0.66) and major affective disorders (OR: 0.65, 95%; CI: 0.62, 0.69) groups. Intervention efforts should target the transition from hospital to home in the subgroup of Veterans with schizophrenia. [ABSTRACT FROM AUTHOR]

Abstract: There is pivotal evidence that tau pathology can be triggered by amyloid-β (Aβ) pathology in experimental systems. On the other side, studies on human brain specimen have elucidated that tau pathology may occur before amyloid pathology is present indicating that in principle tau pathology could also trigger Aβ aggregation. To address this question, we have crossed 5XFAD mice coexpressing human mutant APP695 with the Swedish, Florida, and London mutations and human mutant presenilin-1 (PS1) with the M146L and L286V mutations with the PS19 model overexpressing human mutant tau with the P301S mutation. The resulting triple transgenic model 5XFAD/PS19 has been characterized at 3 and 9 months of age. A dramatic aggravation of hyperphosphorylated tau pathology together with a dramatically increased inflammatory response and a loss of synapses and hippocampal CA1 neurons in aged 5XFAD/PS19 mice were observed. Extracellular amyloid deposits were unaltered. These data support the assumption of tau pathology being downstream of amyloid pathology, suggesting that both pathologies together trigger the severe neuron loss in the hippocampus in the 5XFAD/PS19 mouse model. [Copyright &y& Elsevier]

Pyroglutamate-modified amyloid-β (AβpE3) peptides are gaining considerable attention as potential key participants in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Transgenic mice that produce high levels of AβpE3-42 show severe neuron loss. Recent in vitro and in vivo experiments have proven that the enzyme glutaminyl cyclase catalyzes the formation of AβpE3. In this minireview, we summarize the current knowledge on AβpE3, discussing its discovery, biochemical properties, molecular events determining formation, prevalence in the brains of AD patients, Alzheimer mouse models, and potential as a target for therapy and as a diagnostic marker. [ABSTRACT FROM AUTHOR]

Adults with serious mental illness (SMI) have high rates of cardiovascular disease, particularly heart failure, which contribute to premature mortality. The aims were to examine 90- and 365-day all-cause medical or surgical hospital readmission in Veterans with SMI discharged from a heart failure hospitalization. The exploratory aim was to evaluate 180-day post-discharge engagement in cardiac rehabilitation, an effective intervention for heart failure. This study used administrative data from the Veterans Health Administration (VHA) and Centers for Medicare & Medicaid Services between 2011 and 2019. SMI status and medical comorbidity were assessed in the year prior to hospitalization. Cox proportional hazards models (competing risk of death) were used to evaluate the relationship between SMI status and outcomes. Models were adjusted for VHA hospital site, demographics, and medical characteristics. The sample comprised 189,767 Veterans of which 23,671 (12.5%) had SMI. Compared to those without SMI, Veterans with SMI had significantly higher readmission rates at 90 (16.1% vs. 13.9%) and 365 (42.6% vs. 37.1%) days. After adjustment, risk of readmission remained significant (90 days: HR: 1.07, 95% CI: 1.03, 1.11; 365 days: HR: 1.10, 95% CI: 1.07, 1.12). SMI status was not significantly associated with 180-day cardiac rehabilitation engagement (HR: 0.98, 95% CI: 0.91, 1.07). Veterans with SMI and heart failure have higher 90- and 365-day hospital readmission rates even after adjustment. There were no differences in cardiac rehabilitation engagement based on SMI status. Future work should consider a broader range of post-discharge interventions to understand contributors to readmission. • Veterans with SMI and heart failure have high medical burden. • Veterans with SMI and heart failure are at increased risk for hospital readmission. • Cardiac rehabilitation engagement is low after a heart failure hospitalization. [ABSTRACT FROM AUTHOR]

Alzheimer's disease (AD) is strongly associated with microglia-induced neuroinflammation. Particularly, Aβ plaque-associated microglia take on an “activated” morphology. However, the function and phenotype of these Aβ plaque-associated microglia are not well understood. We show hyperreactivity of Aβ plaque-associated microglia upon systemic inflammation in transgenic AD mouse models (i.e., 5XFAD and APP23). Gene expression profiling of Aβ plaque-associated microglia (major histocompatibility complex II + microglia) isolated from 5XFAD mice revealed a proinflammatory phenotype. The upregulated genes involved in the biological processes (gene ontology terms) included: “immune response to external stimulus” such as Axl , Cd63 , Egr2 , and Lgals3 , “cell motility”, such as Ccl3 , Ccl4 , Cxcr4 , and Sdc3 , “cell differentiation”, and “system development”, such as St14 , Trpm1 , and Spp1 . In human AD tissue with similar Braak stages, expression of phagocytic markers and AD-associated genes, including HLA-DRA , APOE , AXL , TREM2 , and TYROBP , was higher in laser-captured early-onset AD (EOAD) plaques than in late-onset AD plaques. Interestingly, the nonplaque parenchyma of both EOAD and late-onset AD brains, the expression of above-mentioned markers were similarly low. Here, we provide evidence that Aβ plaque-associated microglia are hyperreactive in their immune response and phagocytosis in the transgenic AD mice as well as in EOAD brain tissue. We suggest that Aβ plaque-associated microglia are the primary source of neuroinflammation related to AD pathology. [ABSTRACT FROM AUTHOR]

Pyroglutamate-modified Aβ peptides at amino acid position three (AβpE3-42) are gaining considerable attention as potential key players in the pathogenesis of Alzheimer disease (AD). AβpE3-42 is abundant in AD brain and has a high aggregation propensity, stability and cellular toxicity. The aim of the present work was to study the direct effect of elevated Aβ pE3-42 levels on ongoing AD pathology using transgenic mouse models. To this end, we generated a novel mouse model (TBA42) that produces Aβ pE3-42 TBA42 mice showed age-dependent behavioral deficits and Aβ pE3-42 accumulation. The Aβ profile of an established AD mouse model, 5XFAD, was characterized using immunoprecipitation followed by mass spectrometry. Brains from 5XFAD mice demonstrated a heterogeneous mixture of full-length, N-terminal truncated, and modified Aβ peptides: Aβ1-42, Aβ1-40, Aβ pE3-42, Aβ pE3-42 Aβ pE3-42, Aβ 4-42, and Aβ 5-42 5XFAD and TBA42 mice were then crossed to generate transgenic FAD42 mice. At 6 months of age, FAD42 mice showed an aggravated behavioral phenotype compared with single transgenic 5XFAD or TBA42 mice. ELISA and plaque load measurements revealed thatAβpE3 levels were elevated in FAD42 mice. No change in Aβ x-42 or other Aβ isoforms was discovered by ELISA and mass spectrometry. These observations argue for a seeding effect of Aβ pE3-42in FAD42 mice. [ABSTRACT FROM AUTHOR]

Abstract: Context: Laser treatment of benign prostatic obstruction (BPO) has become more prevalent in recent years. Although multiple surgical approaches exist, there is confusion about laser–tissue interaction, especially in terms of physical aspects and with respect to the optimal treatment modality. Objective: To compare available laser systems with respect to physical fundamentals and to discuss the similarities and differences among introduced laser devices. Evidence acquisition: The paper is based on the second expert meeting on the laser treatment of BPO organised by the European Association of Urology Section of Uro-Technology. A systematic literature search was also carried out to cover the topic of laser treatment of BPO extensively. Evidence synthesis: The principles of generation of laser radiation, laser fibre construction, the types of energy emission, and laser–tissue interaction are discussed in detail for the laser systems used in the treatment of BPO. The most relevant laser systems are compared and their physical properties discussed in depth. Conclusions: Laser treatment of BPO is gaining widespread acceptance. Detailed knowledge of the physical principles allows the surgeon to discriminate between available laser systems and their possible pitfalls to guarantee high safety levels for the patient. [Copyright &y& Elsevier]

Abstract: Environmental enrichment has been used in a variety of transgenic mouse models of Alzheimer''s disease (AD), however, with conflicting results. Here we studied the influence of environmental enrichment in a severely affected AD mouse model, showing a multiplicity of pathological alterations including hippocampal neuron loss. APP/PS1KI and wild type (WT) control mice were housed under standard conditions or in enriched cages equipped with various objects and running wheels. Amyloid plaque load, motor and working memory performance, axonopathy, as well as CA1 neuron number and hippocampal neurogenesis were assessed. Although a partial improvement in motor performance was observed, 4 months of enriched housing showed no beneficial effects in terms of working memory, Aβ plaque pathology, or neuron loss in APP/PS1KI mice. In addition, no changes in hippocampal neurogenesis and even an aggravation of the axonal phenotype were detected with a tendency toward a premature death. The APP/PS1KI model represents a model for mild to severe AD showing early behavioral deficits starting at 2 months of age with fast deterioration. Therefore our data might suggest that physical activity and enriched environment might be more beneficial in patients with mild cognitive impairment than in patients with incipient AD. [Copyright &y& Elsevier]

Abstract: In the present work, we investigated the level of IgM autoantibodies directed against different Aβ epitopes as potential diagnostic biomarker for Alzheimer''s disease (AD). Anti-Aβ autoantibody levels were measured in 75 plasma samples from patients with AD, individuals with mild cognitive impairment (MCI), and healthy age- and sex-matched controls (HC). To validate the presence of anti-Aβ IgMs, pooled plasma samples were subjected to gel-filtration analysis. The mean level of pGluAβ-IgM (N-terminal truncated starting at position three with pyroglutamate) was significantly decreased in AD patients as compared to HC. In the group of MCI patients there was a significant positive correlation between pGluAβ-IgM and cognitive decline analyzed by MMSE (rho=0.58, d.f.=13, p =0.022). These observations indicate that the level of IgM autoantibodies against pGluAβ is a promising plasma biomarker for AD and correlates with the cognitive status of individuals at risk to develop AD. [Copyright &y& Elsevier]

Pyroglutamate-modified Aβ (AβpE3-42) peptides are gaining considerable attention as potential key players in the pathology of Alzheimer disease (AD) due to their abundance in AD brain, high aggregation propensity, stability, and cellular toxicity. Overexpressing AβpE3-42 induced a severe neuron loss and neurological phenotype in TBA2 mice. In vitro and in vivo experiments have recently proven that the enzyme glutaminyl cyclase (QC) catalyzes the formation of AβpE3-42. The aim of the present work was to analyze the role of QC in an AD mouse model with abundant AβpE3-42 formation. 5XFAD mice were crossed with transgenic mice expressing human QC (hQC) under the control of the Thy1 promoter. 5XFAD/hQC bigenic mice showed significant elevation in TBS, SDS, and formic acid-soluble AβpE3-42 peptides and aggregation in plaques. In 6-month-old 5XFAD/hQC mice, a significant motor and working memory impairment developed compared with 5XFAD. The contribution of endogenous QC was studied by generating 5XFAD/QC-KO mice (mouse QC knock-out). 5XFAD/QC-KO mice showed a significant rescue of the wild-type mice behavioral phenotype, demonstrating the important contribution of endogenous mouse QC and transgenic overexpressed QC. These data clearly demonstrate that QC is crucial for modulating AβpE3-42 levels in vivo and prove on a genetic base the concept that reduction of QC activity is a promising new therapeutic approach for AD. [ABSTRACT FROM AUTHOR]

N-terminally truncated Aβ peptides starting with pyroglutamate (AβpE3) represent a major fraction of all Aβ peptides in the brain of Alzheimer disease (AD) patients. AβpE3 has a higher aggregation propensity and stability and shows increased toxicity compared with full-length Aβ. In the present work, we generated a novel monoclonal antibody (9D5) that selectively recognizes oligomeric assemblies of AβpE3 and studied the potential involvement of oligomeric AβpE3 in vivo using transgenic mouse models as well as human brains from sporadic and familial AD cases. 9D5 showed an unusual staining pattern with almost nondetectable plaques in sporadic AD patients and non-demented controls. Interestingly, in sporadic and familial AD cases prominent intraneuronal and blood vessel staining was observed. Using a novel sandwich ELISA significantly decreased levels of oligomers in plasma samples from patients with AD compared with healthy controls were identified. Moreover, passive immunization of 5XFAD mice with 9D5 significantly reduced overall Aβ plaque load and AβpE3 levels, and normalized behavioral deficits. These data indicate that 9D5 is a therapeutically and diagnostically effective monoclonal antibody targeting low molecular weight AβpE3 oligomers. [ABSTRACT FROM AUTHOR]

Abstract: The disturbed metabolism of β-amyloid peptides generated from amyloid precursor protein is widely considered as a main factor during the pathogenesis of Alzheimer''s disease. A neuropathological hallmark in the brains from cases with Alzheimer''s disease are senile plaques mainly composed of hardly soluble β-amyloid peptides comprising up to 43 amino acids. Age-dependent cortical β-amyloidosis was also shown in several transgenic mice and old individuals from various mammalian species, e.g., non-human primates. β-Amyloid1–42 is believed to be the main component in the core of senile plaques, whereas less hydrophobic β-amyloid1–40 predominantly occurs in the outer rim of plaques. Amino-terminally truncated pyroglutamyl-β-amyloidpE3–x was recently found to be a β-amyloid species of high relevance to the progression of the disease. While a few biochemical studies provided data on the co-occurrence of several β-amyloid forms, their concomitant histochemical detection is still lacking. Here, we present a novel triple immunofluorescence labelling of amino- and differently carboxy-terminally truncated β-amyloid peptides in cortical plaques from a case with Alzheimer''s disease, senile macaques and baboons, and triple transgenic mice with age-dependent β-amyloidosis and tau hyperphosphorylation. Additionally, β-amyloidpE3–x and total β-amyloid were concomitantly detected with β-amyloid peptides ending with amino acid 40 or 42, respectively. Simultaneous staining of several β-amyloid species reveals for instance vascular amyloid containing β-amyloidpE3–x in Alzheimer''s disease and monkeys, and may contribute to the further elucidation of β-amyloidosis in neurodegenerative disorders and animal models. [Copyright &y& Elsevier]

Abstract: Inflammatory processes are considered to play an important role in the progression of neurodegenerative changes in Alzheimer''s disease (AD). In the present study, we performed a systematic expression analysis of various inflammatory and oxidative stress markers in pre-symptomatic and diseased APP/PS1KI mice. This mouse model has been previously shown to harbor severe pathological alterations, including behavioral deficits, axonal degeneration and hippocampal neuron loss starting at the age of 6 months. While the expression levels of most markers remained unchanged in 2-month-old APP/PS1KI mice, at the age of 6 months different astro- and microglia markers including GFAP, Cathepsin D, members of the Toll-like receptor (Tlr) family, TGFβ-1 and osteopontin were up-regulated. In addition, oxidative stress markers, including the metallothioneins, were also significantly elevated at that time point. As expected, both brain and spinal cord were affected, the latter showing early activation of GFAP-positive astrocytes and Iba1-positive microglia in white matter fiber tracts, which might contribute to the previously reported axonal defects in this mouse model. These data add further evidence to the assumption that inflammatory processes are tightly associated with axonal degeneration and neuron loss, as is evident in the APP/PS1KI mouse model. [Copyright &y& Elsevier]

The β-amyloid precursor protein (APP) represents a type I transmembrane glycoprotein that is ubiquitously expressed. In the brain, it is a key player in the molecular pathogenesis of Alzheimer disease. Its physiological function is however less well understood. Previous studies showed that APP is up-regulated in prostate, colon, pancreatic tumor, and oral squamous cell carcinoma. In this study, we show that APP has an essential role in growth control of pancreatic and colon cancer. Abundant APP staining was found in human pancreatic adenocarcinoma and colon cancer tissue. Interestingly, treating pancreatic and colon cancer cells with valproic acid (VPA, 2-propylpentanoic acid), a known histone deacetylase (HDAC) inhibitor, leads to up-regulation of GRP78, an endoplasmic reticulum chaperone immunoglobulin-binding protein. GRP78 is involved in APP maturation and inhibition of tumor cell growth by down-regulation of APP and secreted soluble APPot. Trichostatin A, a pan-HDAC inhibitor, also lowered APP and increased GRP78 levels. In contrast, treating cells with valpromide, a VPA derivative lacking HDAC inhibitory properties, had no effect on APP levels. VPA did not modify the level of epidermal growth factor receptor, another type I transmembrane protein, and APLP2, a member of the APP family, demonstrating the specificity of the VPA effect on APP. Small interfering RNA-mediated knockdown of APP also resulted in significantly decreased cell growth. Based on these observations, the data suggest that APP down-regulation via HDAC inhibition provides a novel mechanism for pancreatic and colon cancer therapy. [ABSTRACT FROM AUTHOR]

Abstract: The APP/PS1ki mouse model for Alzheimer''s disease (AD) exhibits robust brain and spinal cord axonal degeneration and hippocampal CA1 neuron loss starting at 6 months of age. It expresses human mutant APP751 with the Swedish and London mutations together with two FAD-linked knocked-in mutations (PS1 M233T and PS1 L235P) in the murine PS1 gene. The present report covers a phenotypical analysis of this model using either behavioral tests for working memory and motor performance, as well as an analysis of weight development and body shape. At the age of 6 months, a dramatic, age-dependent change in all of these properties and characteristics was observed, accompanied by a significantly reduced ability to perform working memory and motor tasks. The APP/PS1ki mice were smaller and showed development of a thoracolumbar kyphosis, together with an incremental loss of body weight. While 2-month-old APP/PS1ki mice were inconspicuous in all of these tasks and properties, there is a massive age-related impairment in all tested behavioral paradigms. We have previously reported robust axonal degeneration in brain and spinal cord, as well as abundant hippocampal CA1 neuron loss starting at 6 months of age in the APP/PS1ki mouse model, which coincides with the onset of motor and memory deficits described in the present report. [Copyright &y& Elsevier]

Sortilin-related receptor with A-type repeats (SORLA) is a sorting receptor that impairs processing of amyloid precursor protein (APP) to soluble (s) APP and to the amyloid β-peptide in cultured neurons and is poorly expressed in patients with Alzheimer disease (AD). Here, we evaluated the consequences of Sorla gene defects on brain anatomy and function using mouse models of receptor deficiency. In line with a protective role for SORLA in APP metabolism, lack of the receptor results in increased amyloidogenic processing of endogenous APP and in aggravated plaque deposition when introduced into PDAPP mice expressing mutant human APP. Surprisingly, increased levels of sAPP caused by receptor deficiency correlate with profound stimulation of neuronal ERK signaling and with enhanced neurogenesis, providing in vivo support for neurotrophic functions of sAPP. Our data document a role for SORLA not only in control of plaque burden but also in APP-dependent neuronal signaling and suggest a molecular explanation for increased neurogenesis observed in some AD patients. [ABSTRACT FROM AUTHOR]

Abstract: Some neurodegenerative diseases including Alzheimer''s disease (AD) and amyotrophic lateral sclerosis (ALS) exhibit prominent defects in axonal transport. These defects can manifest as axonal swellings or spheroids, which correspond to axonal enlargements and aberrant accumulation of axonal cargoes, cytoskeletal proteins and lipids. Recently, a controversial scientific debate focussed on the issue whether Aβ serves as a trigger for aberrant axonal transport in the pathophysiology of AD. Prominent axonopathy has been shown to be induced by overexpression of proteins involved in several neurodegenerative diseases. Neurofilament, apolipoprotein E, Niemann-Pick protein and Tau transgenic mice with axonal trafficking deficits have been reported. Furthermore, motor deficits are frequently observed in patients with AD, which has been attributed to the typical tauopathy in post-mortem brain tissue. In the present report, we analyzed axonal neuropathology in the brain and spinal cord of a transgenic mouse model with abundant intraneuronal Aβ42 production and provide compelling evidence for axonal degeneration. The APP/PS1ki mice showed characteristic axonal swellings, spheroids, axonal demyelination and ovoids, which are myelin remnants of degenerated nerve fibers in an age-dependent manner. Abundant accumulation of intraneuronal N-modified Aβ, Thioflavin S-positive material and ubiquitin was found within the somatodendritic compartment of neurons. We conclude that the intraneuronal accumulation of Aβ-amyloid peptides is followed by axonal degeneration, and thus might be a causative factor for the axonal changes seen in AD. [Copyright &y& Elsevier]