The adult mammalian central nervous system (CNS) is generally considered as repair restricted organ with limited capacities to regenerate lost cells and to successfully integrate them into damaged nerve tracts. Despite the presence of endogenous immature cell types that can be activated upon injury or in disease cell replacement generally remains insufficient, undirected, or lost cell types are not properly generated. This limitation also accounts for the myelin repair capacity that still constitutes the default regenerative activity at least in inflammatory demyelinating conditions. Ever since the discovery of endogenous neural stem cells (NSCs) residing within specific niches of the adult brain, as well as the description of procedures to either isolate and propagate or artificially induce NSCs from various origins ex vivo, the field has been rejuvenated. Various sources of NSCs have been investigated and applied in current neuropathological paradigms aiming at the replacement of lost cells and the restoration of functionality based on successful integration. Whereas directing and supporting stem cells residing in brain niches constitutes one possible approach many investigations addressed their potential upon transplantation. Given the heterogeneity of these studies related to the nature of grafted cells, the local CNS environment, and applied implantation procedures we here set out to review and compare their applied protocols in order to evaluate rate-limiting parameters. Based on our compilation, we conclude that in healthy CNS tissue region specific cues dominate cell fate decisions. However, although increasing evidence points to the capacity of transplanted NSCs to reflect the regenerative need of an injury environment, a still heterogenic picture emerges when analyzing transplantation outcomes in injury or disease models. These are likely due to methodological differences despite preserved injury environments. Based on this meta-analysis, we suggest future NSC transplantation experiments to be conducted in a more comparable way to previous studies and that subsequent analyses must emphasize regional heterogeneity such as accounting for differences in gray versus white matter. Ever since the discovery of naturally occurring neural stem cells (NSCs) residing in discrete niches of the adult mammalian central nervous system (CNS) ,2,3,4,5,While screening the publicly available literature, it became evident that there is a large degree of heterogeneity when it comes to the NSC transplantation procedure itself, related for example to age and species of donor- as well as host tissues, the question whether sorted/enriched cell populations versus mixed cell grafts were applied or concerning time-points at which host tissue and grafted cells were analyzed. Likewise, the localization and type of an injury prior to engraftment of stem cells, as well as their positioning within lesion zones additionally influence cellular integration and differentiation. It would therefore be important to define rate limiting and dominating parameters to ensure a larger degree of comparability across different investigations and to promote the development of protocols that will eventually lead to a successful clinical translation.Clinical research depends on animal models, which mimic human disease or injury. For neuropathological studies of the CNS various animal models such as acute and chronic spinal cord injury (SCI); traumatic brain injury (TBI); inflammatory-, genetically-, or chemically induced demyelination/neurodegeneration have been used to assess the impact of NSC transplantation on either lesion amelioration or tissue regeneration. The outcome of these studies shows a surprising degree of variability in terms of cell fate acquisition, migration within the host tissue as well as the implanted cell’s potential to fully mature 5 or P75 old mice for transplantation into the striatum, motor cortex, and lateral posterior thalamic nucleus, Seidenfaden and colleagues showed that transplanted cell survival is independent of the donor animal age—at least when comparing immature postnatal- to young adult brains . FurtherA related transplantation study used rats instead of mice for both donor cells as well as host animals . HoweverFurther support for the assumption that exogenous factors influence the fate of transplanted NSCs  resultedFor a successful treatment of neurological conditions such as multiple sclerosis (MS) or adrenoleukodystrophies transplanted NSCs would have to distribute well within diseased brains in order to access multiple and irregularly dispersed lesions. Active migration within the brain parenchyma appears indeed to be a rare feature of implanted NSCs as for example transplantation of SVZ-derived NSCs into neighboring SVZ regions of adult healthy mice did not result in any observable migration activities . TransplSupporting evidence that brain region specific cues act across different species arose from a subsequent study in which embryonic human NSCs (huNSCs) were applied to injury-free models . Here, dThe astonishing impact especially the RMS exerts on transplanted NSCs was corroborated by yet another study . This inComparing outcomes of NSC transplantation in different neuropathological or injury inflicted models is important in order to understand the adaptability NSCs are capable of and also for the development of CNS repair strategies. Nevertheless, due to the high degree of variation and heterogeneity across the different model systems this section will focus on selected models representing both common and rare as well as global and focal pathologies. Working out the details between different injury models, and taking into account heterogenic responses of different brain regions depends on comparable starting conditions. This includes information on donor age, on the particular donor stem cell niche, on isolated cell types and whether they were propagated in culture or whether genetic manipulation was applied prior to transplantation. Moreover, variations deriving from different model systems will also be considered.Treatment of hereditary white matter disorders characterized by abnormal or complete absence of myelin due to mutations in genes encoding for myelin proteins (such as in Pelizaeus-Merzbacher disease) will most likely depend on engraftment of healthy cells giving rise to functionally unimpaired myelin forming oligodendrocytes. In shiverer mice (shi) homozygous mutations in the myelin basic protein (MBP) gene lead to the absence of MBP expression and consequently to low levels of compact and functional myelin ,21 and ishi/shi) were used as host animals, which in terms of methodology makes these studies highly comparable. Therefore, the reason for such differential fate outcome remains obscure.However, intracerebroventricular transplantation of the same NSC cell line (C17.2) into shi mice of comparable age (P1-P3) resulted in mainly neuronal differentiation . While tStudies in which transplantation experiments were performed using different  stem cell types but exclusively applying a single neuropathological model are of special value since methodological differences can be ruled out. When adult forebrain SVZ neural precursor cells (aNPCs) were grafted into the dysmyelinated spinal cord of shiverer rats, the majority differentiated into oligodendroglial cells and even into mature myelinating OLs . In contTraumatic brain injury (TBI) results from forced impact to the skull and brain, which leads to a primary- (direct negative influence on tissue architecture and homeostasis) as well as a secondary  injury . Due to The study by Koutsoudaki and colleagues elegantly demonstrated the non-necessity of NSC modulation prior to transplantation into injured adult mouse brains. Upon TBI to the hippocampus by stabbing multiple times 2 mm deep through the cortex, corpus callosum, and hippocampus, non-modified (reporter-gene expression only) and insulin like growth factor 1 (IGF1) overexpressing NSCs  were transplanted close to the lesion site. Considering fate outcome as well as functional improvement , no differences between IGF1 producing and reporter gene only expressing NSCs were observed. Both cell populations ameliorated injury-induced spatial learning deficits and in both cases transplanted NSCs mainly differentiated into oligodendroglial cells . As in sIn contrast to the TBI wound induced by a blunt-end needle, which also disrupts WM structures , the modIn a comparable experimental set up (modified Feeney method) neonatal mouse hippocampus-derived NSCs were transplanted 24 h after injury into the pericontusional region . SimilarTemporal lobe epilepsy (TLE) is a common form seen in about 30% of epileptic patients. By injecting kainic acid (KA) into the rodent hippocampus or the SVZ, neurodegeneration is induced and neuronal cell death and functional impairments similar to TLE patients can be mimicked. While NSC transplantation has also been investigated in terms of trophic support these NSCs can confer to the damaged environment, this section will focus on the aspect of NSC mediated cell replacement and fate choice.Since kainate induced hippocampal degeneration represents a focal CNS injury, transplantation of P5 mouse SVZ-derived NSCs into the hippocampus close to the injection site resulted in only minor migration towards the lesion area . Stem ceWhile transplantation of NSCs into the kainate-induced neurodegenerative hippocampus resulted in mostly neuronal differentiation and ameliorated cognitive function , anotherA further TLE study also reported primarily astroglial fate choices although NSCs were transplanted into an acute TLE model . A changAnother interesting finding is that SVZ-derived NSCs transplanted into healthy non-injured hippocampi were also located close to the SVZ several weeks after transplantation —a distriSly disease is a rare hereditary lysosomal storage disorder, characterized by the deficiency in β-glucuronidase (GUSB) and subsequent accumulation of glycosaminglycans in many organs including the brain leading to mental retardation. Applying NSCs as early as technically feasible might provide a potential therapeutic approach in order to restore global dysfunction of the developing brain. The mucopolysaccharidosis VII (MPS VII) mouse strain mimics human sly disease pathological features. Upon transplantation of GUSB-expressing C17.2 NSCs into lateral ventricles of neonatal MPS VII mice, cells distributed and integrated in the whole brain and no tumorigenesis was observed . WidesprThe lack of oxygen supply in the brain results in ischemic stroke, leading to irreversible neuronal damage . IschemiTransplantation of neurosphere-derived cells from neonatal mice hence containing NSCs, various progenitors and more differentiated cells  into theRegarding differences in the microenvironment of ischemic brain regions over time, Darsalia and colleagues compared the differential outcome of intrastriatally transplanted human fetal striatal NSCs 48 h and six weeks after stroke. Transplantation after 48 h following stroke resulted in a higher NSC survival rate as compared to transplantation at the later time-point. However, different time-points did not affect the extent of migration, differentiation and proliferation. Interestingly, analysis of neuronal fate acquisition revealed no change in the percentage of Dcx-positive neuroblasts but for both transplantation time-points the percentage was lower as compared to injury-free animals . Such ob35–55) peptide induced EAE, which leads to a T-cell mediated autoimmune response towards oligodendrocytes with the first symptoms appearing ten days after initial immunization.Multiple sclerosis (MS) is an autoimmune disease characterized by oligodendrocyte and myelin loss, which ultimately leads to axonal degeneration and subsequent sensory, motor, and cognitive dysfunction . The mosIntracerebroventricular transplantation of human embryonic stem cell-derived early multipotent neural precursor cells (hESC-NPCs) demonstrated robust migration into the host WM, which led to significantly reduced clinical sings of EAE in host mice . The benFurther evidence for a high migratory activity of implanted cells in the EAE brain derived from a report on human induced pluripotent stem cell-derived NSCs (iPSC-NSCs) having migrated into the dentate gyrus one month following intraventricular transplantation in EAE mice . Co-locaMinor regeneration promoting effects using allogenic NSCs were also reported for a chronic EAE model, into which transplantation was performed 40 days post-immunization. Here, treatment with non-modified bone marrow-derived (BM) NSCs (derived from six- to eight-week-old mice)  blocked While the two previous studies report minor regeneration promoting effects using allogenic or naïve NSCs in EAE mice, Einstein and colleagues could show that intraventricularly transplanted striatal newborn rat multipotential NSCs migrated into inflamed WM tracts and subsequently differentiated into glial cells in EAE rats. This transplantation strategy resulted in a reduced inflammation of the host brain and ameliorated the disease course. Whether beneficial effects were due to additional processes attributed to particularly the rat system remains open.Intraventricular transplantation of both, glial-derived neurotrophic factor (GDNF) overexpressing- (GDNF-NSCs) or naïve newborn rat cerebrum-derived NSCs ten days following EAE induction led to a delayed disease onset and significant reduction of clinical EAE signs . More spwww.alzforum.org) [Neurodegeneration in Alzheimer´s disease (AD) results in learning deficits and dementia. In a murine AD model (APP/PS1 mice), neuron-specific Thy1 promotor driving the co-expression of KM670/671NL mutated amyloid precursor protein (APP) and of L166P mutated presenilin-1 (PS1) leads to human amyloid depositions and local neuronal loss in the dentate gyrus ,50. The rum.org) ,53,54,55rum.org) ,60,61,62rum.org) ,57,61,62rum.org) . Using arum.org) . The obsInterestingly, most of the compiled studies report that transplanted NSCs showed high migratory behavior leaving injection sites ,63,64,65Using a chemical model to mimic AD related neuropathological features by okadaic acid injection into the lateral ventricles  only traHuntington´s disease (HD) is an inherited neurodegenerative disease caused by the progressive loss of GABAergic medium spiny neurons (MSNs) in the striatum. Injection of 3-nitropropionic acid (3-NP) into the striatum serves as an animal model to mimic HD symptoms and related neurodegenerative aspects. Transplantation of human NSCs  into the injured striatum one week prior to the injury resulted in decreased loss of striatal neurons as well as the appearance of calbindin-expressing  donor cell-derived neurons . Upon imSpinal cord injury (SCI) is a devastating neurological condition, which is caused by a traumatic impact to the spinal cord. It results in permanent impairment of motor- and sensory functions due to the interruption of descending and ascending nerve fiber tracts. Local cell loss at sites of injury is followed by glial scar formation and accompanied by inflammation which prevent regeneration of transected axons and exert an additional negative impact on functionality and survival of remote neurons ,75. StemIn this regard, we compared data on fate acquisition of transplanted NSCs from two methodologically different SCI models. Compression or contusion used to induce broader and probably medically more relevant spinal cord lesions is compared to more defined injuries resulting from spinal cord hemisection or complete transection. Both models affect spinal cord integrity and lead to motor and sensory dysfunction while differing in terms of lesion volume and extent of secondary damage. Transplantation of various NSCs indeed led to the generation of different cell fates correlating with the type of evoked injury.Interestingly, rodent and human NSCs transplanted into a compression or a contusion lesion preferentially differentiated into oligodendrocytes ,89,90,91While most NSC transplantation based SCI studies focused on rodent models, Iwanami and colleagues used a primate contusion model. Upon cervical contusion in marmosets and subsequent transplantation of human NSCs, assessment of fate acquisition of the engrafted NSCs showed the following distribution: 46% GFAP-positive astrocytes, 25% nestin-positive stem cells, 21% β-III-Tub-positive neurons, and 5% Olig2-positive oligodendroglial cells . Since iMigration of transplanted NSCs towards an injury site, into lesion zones or close to demyelinated axonal fibers is key for a potential beneficial role of transplanted NSCs in terms of local neurotrophic factor secretion or remyelination. Considering the migratory potential of transplanted NSCs, it was found that migration exclusively occurs in spinal cords with a contusion or compression injury ,99,103. Despite the well described self-renewing potential of  stem cells in vitro as well as in their discrete niches in vivo, transplanted stem cells showed little or no proliferation activities within host tissues in all SCI studies considered here ,91,95,98The aforementioned studies revealing differences and similarities in different SCI models all used subacute or acute application conditions, in that NSC transplantation was performed immediately or shortly after injury. However, this does not necessarily reflect a patient’s situation who will first receive emergency surgery in order to stabilize general conditions and to avoid secondary damage preceding possible regeneration directed therapies. Moreover, for autologous stem cell transplantation a timely application of appropriate cell numbers is not feasible. Investigating chronic SCI models in which cells are transplanted several weeks after SCI might therefore be more relevant in terms of clinical translation and feasibility. In this regard, not only the type of induced injury (pressure or cut) appears to be important but also the disease process seems to account for the NSC fate. This particular question was addressed by several groups comparing chronic  to a subacute (days after injury) transplantation approaches. In two studies, a lower survival rate of NSCs transplanted after four and eight weeks into contusion lesions compared to a subacute transplantation process was observed ,86. WhilOf note, given that at least for transplanted OPCs heterogenic responses in gray vs. white matter have been described , a systeThe high complexity of adult mammalian central nervous systems and the low degree of intrinsic repair capacity results in devastating functional impairments and persisting disabilities in most neuropathologies. The discovery of neural stem cells and their potential to give rise to all cell lineages of the CNS has revived the field in terms of functional cell replacement. Initial concerns related to exogenously applied NSCs and possible adverse effects were refuted as the majority of NSC transplantation studies revealed no tumor formation. Interestingly, studies investigating the outcome of NSC transplantations into healthy CNS tissue revealed dominant region-specific cues instructing the grafts. Despite a great heterogeneity among different CNS lesion models, transplanted NSC migration towards lesion sites and subsequent differentiation into to be replenished cell types are common observations in the majority of neuropathological models. These observations raise hope for the development of NSC-mediated CNS regeneration therapies as most neural stem cell types seem to be sensible to injury environments and their requirements and since even delayed NSC applications can confer functional benefits.


Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs. Microvascular and vasospastic angina are relevant but may not be diagnosed without measuring coronary vascular function. The relationship between cardiovascular magnetic resonance (CMR)-derived myocardial blood flow (MBF) and reference invasive coronary function tests is uncertain. We hypothesise that multiparametric CMR assessment will be clinically useful in the ANOCA diagnostic pathway.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) trial is a prospective, blinded, randomised, sham-controlled study comparing two management approaches in patients with ANOCA. We aim to recruit consecutive patients with stable angina undergoing elective invasive coronary angiography. Eligible patients with ANOCA (n=150) will be randomised to invasive coronary artery function-guided diagnosis and treatment (intervention group) or not (control group). Based on these test results, patients will be stratified into disease endotypes: microvascular angina, vasospastic angina, mixed microvascular/vasospastic angina, obstructive epicardial coronary artery disease and non-cardiac chest pain. After randomisation in CorMicA, subjects will be invited to participate in the Coronary Microvascular Angina Cardiac Magnetic Resonance Imaging (CorCMR) substudy. Patients will undergo multiparametric CMR and have assessments of MBF (using a novel pixel-wise fully quantitative method), left ventricular function and mass, and tissue characterisation (T1 mapping and late gadolinium enhancement imaging). Abnormalities of myocardial perfusion and associations between MBF and invasive coronary artery function tests will be assessed. The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests.The CorMicA trial and CorCMR substudy have UK REC approval (ref.16/WS/0192).NCT03193294. Angina with no obstructive coronary artery disease (ANOCA) is a common syndrome with unmet clinical needs.A significant proportion of these patients may suffer from microvascular and vasospastic angina.Diagnosis in this patients may be challending, are there are uncertain associations between the results of reference invasive diagnostic tests and the non-invasive ischaemia test results.Novel CMR methods for measuring myocardial blood flow have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina.The CorCMR substudy represents the largest cohort of ANOCA patients with paired multiparametric CMR and comprehensive invasive coronary vascular function tests. CorCMR will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in patients with ANOCA.In contrast to the reference standard invasive tests of coronary artery function, non-invasive imaging is safer and more acceptable to patients.The CorCMR sub-study presents a unique opportunity to assess and validate the diagnostic accuracy of fully-quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.Ischaemic heart disease is the leading cause of mortality standardised by age and sex.Patients with angina and no obstructive coronary artery disease (ANOCA) present a diagnostic conundrum.The underlying pathogenesis in patients with ANOCA is unclear, as specific disease endotypes are not routinely tested for. CMD may result from coronary structural abnormalities, whereby decreased capillary luminal size and number result in increased microvascular resistance to myocardial blood flow (MBF) and reduced vasodilatory capacity.Abnormalities of coronary vascular function portend a worse prognosis in patients with both obstructive epicardial CAD and ANOCA.Diagnosis of coronary microvascular and vasomotor dysfunction is challenging due to the heterogeneity of underlying disease mechanisms, the potentially patchy distribution of disease throughout the myocardium, and limited spatial resolution of existing diagnostic tests.There is no accepted guideline-directed diagnostic algorithm for coronary vascular dysfunction in routine clinical practice.The available non-invasive ischaemia tests were all validated for the detection of obstructive epicardial CAD. There has been a low yield of inducible myocardial ischaemia in ANOCA patients with traditional non-invasive ischaemia tests .Coronary microvascular disease may be revealed by a deficit in MBF during stress CMR. The spatial distribution of this abnormality typically involves the subendocardium, which is the location of the microvascular plexus.There are uncertain associations between the results of invasive diagnostic tests and the non-invasive ischaemia test results in patients with ANOCA. There is no accepted objective diagnostic threshold for the diagnosis of coronary vascular dysfunction , with either PET or perfusion CMR. Recent studies have investigated the relationships between invasive tests of coronary artery function and semiquantitative perfusion CMR analysis.The Stratified Medical Therapy Using Invasive Coronary Function Testing In Angina (CorMicA) clinical trial is a proof-of-concept, prospective, blinded, randomised, sham-controlled study comparing two management approaches to the clinical problem of patients with ANOCA.The IDP consists of coronary artery function testing using a dual pressure-sensitive and temperature-sensitive guidewire and adenosine followed by intracoronary acetylcholine provocation testing. Assessment of microvascular resistance (IMR), microvascular vasodilatory capacity (resistance reserve ratio (RRR)), epicardial and microvascular vasodilatory capacity (CFR), endothelial function (acetylcholine provocation testing) and epicardial CAD ) will be performed. Following these invasive tests of coronary artery function, patients will be classified into the following ANOCA disease endotypes : (1) micPatients in the control group will receive standard care based on the interpretation of the invasive coronary angiogram alone. Patients in the intervention group will have care based on the disease endotypes disclosed by invasive tests of artery function, and pharmacotherapy linked to the underlying disease endotype will be commenced.Novel CMR methods for measuring MBF have not been validated in patients with ANOCA and underlying microvascular and vasospastic angina. The CorCMR substudy of the CorMicA clinical trial presents a unique opportunity to assess and validate the diagnostic accuracy of fully quantitative stress perfusion CMR in patients with ANOCA and comprehensive invasive coronary artery function testing.We hypothesise that abnormal myocardial perfusion, as revealed by a novel fully quantitative pixel-wise CMR perfusion sequence, will be prevalent in a contemporary UK cohort of patients presenting with ANOCA and that multiparametric CMR imaging will be clinically useful in the diagnostic pathway of patients with ANOCA.We aim to assess the diagnostic validity of quantitative stress perfusion CMR in patients with ANOCA and specific disease endotypes of coronary vascular dysfunction. Our specific aims are to assess:The proportion of ANOCA patients with abnormal myocardial perfusion. There is no accepted threshold for abnormal MPR. Thresholds for reduced CFR of 1.5–2.6 have been described, however <2.0 is commonly used.The diagnostic accuracy of the perfusion CMR metrics for abnormal invasive tests of coronary artery function  and the associations between specific disease endotypes and myocardial perfusion in patients with ANOCA. We also aim to assess the correlation between abnormal CMR-derived perfusion and invasive tests of coronary artery function, of qualitative versus quantitative perfusion methods.The proportion of patients with ANOCA and abnormal myocardial tissue characterisation derived from CMR  imaging) and its association with abnormal myocardial perfusion.The associations between baseline patient characteristics and abnormal myocardial perfusion.The proportion of patients with a change in diagnosis based on quantitative CMR findings, as compared with the initial diagnosis by the attending cardiologist based on the coronary angiogram.Prespecified substudy of the CorMicA stratified medical therapy clinical trial.Patients referred from 14 acute hospitals to two large regional UK hospitals  providing invasive care to all patients in the West of Scotland (population 2.5 million). All CMR studies will be performed at the Golden Jubilee National Hospital.Consecutive outpatients undergoing clinically indicated elective diagnostic angiography for investigation of suspected angina will be screened and invited to participate in the CorMicA trial. Informed consent is obtained before the invasive coronary angiogram. A minimum of 400 consecutive patients undergoing elective invasive coronary angiography is expected to be screened to enrol 150 subjects with ANOCA within 24 months. Consenting patients who are not randomised  will enter a registry. Only patients randomised in the CorMicA trial (both in the intervention and control groups) are eligible to participate in the CorCMR substudy.Age ≥18 years, a clinically indicated plan for invasive coronary angiography and symptoms of angina (according to the Rose angina questionnaire).A non-coronary indication for invasive angiography , obstructive epicardial CAD disease evident in a main coronary artery (diameter >2.5 mm) (defined as diameter stenosis >50% or FFR ≤0.80) and contraindication to contrast-enhanced CMR .Patients will undergo perfusion CMR within 42 days of the CorMicA trial invasive coronary artery function testing. CMR studies will be performed at 1.5 Tesla , and patients will undergo a standardised CMR protocol. All patients will be asked to abstain from caffeine-containing beverages or foodstuffs for 24 hours and vasoactive medications for 48 hours prior to the CMR examination. All scan acquisitions will be spatially coregistered. All CMR analyses will be performed by analysts blinded to the invasive coronary artery function test results. The standardised CMR protocol is demonstrated in Stress and rest first-pass perfusion imaging will be performed using an echo planar imaging dual-sequence investigational perfusion method, which consists of a low resolution arterial input function image, followed by three short axis  myocardial images during each R–R interval.The raw stress and rest perfusion images will be qualitatively assessed for inducible or fixed perfusion defects. Perfusion defects will be reported on a segmental basis according to the American Heart Association 16-segment model.Pixel-wise perfusion maps will be generated and analysed to derive fully quantitative MBF estimates on a pixel-wise basis in mL/g/min of myocardium. The pixel-wise perfusion method uses a series of automated postprocessing steps on the raw Digital Imaging and Communications in Medicine images to generate fully quantitative pixel maps.2] and percentage coefficient of variation of time to maximum signal intensity upslope and time to peak myocardial signal intensity enhancement.The myocardial perfusion dyssynchrony index is a novel perfusion metric that assesses temporal differences in the distribution of gadolinium-based contrast media myocardial wash-in. This index has the potential to increase the diagnostic sensitivity and specificity of perfusion CMR for abnormalities of myocardial perfusion in patients with ANOCA.Fast gradient echo images in the axial, coronal and sagittal planes will be qualitatively assessed for extra cardiac anatomy and pathology and clinically relevant incidental findings.Steady-state free procession ‘cine’ imaging using a trueFISP sequence (multislice single-shot breath-hold true fast imaging) will be performed in the three long-axis and short-axis planes for assessment of LV volumes, function and mass.Native T1 mapping will be performed using a modified look-locker inversion recovery investigational prototype sequence. Images will be obtained in three short-axis images . T1 mapping will be performed pre- and post-gadolinium contrast to assess the myocardial native T1 relaxation time and estimate the myocardial extracellular volume (ECV) in both the mid-septum and globally.LGE imaging will be performed using a segmented phase-sensitive inversion recovery turbo fast low-angle shot imaging sequence.Abnormal myocardial perfusion reserve .A summary of the secondary outcomes is shown in Box 2.LV EFLVEDVLV EDV indexLV ESVLV ESV indexLV massLV mass indexLV COLV CO index2)Left atrial area (cmLeft atria dilated (Y/N)2)Right atrial area (cmRight atria dilated (Y/N)Abnormal perfusion (Y/N)Number of abnormal segments (n)Transmurality of perfusion defects (%)Pattern Global MPR <2.0 (Y/N)Segmental/AHA MPRGlobal stress and rest MBFSegmental/AHA territory stress and rest MBFGlobal stress endocardial:epicardial MPR ratioSegmental/AHA territory endocardial:epicardial MPR ratioMyocardial perfusion dyssynchrony index Splenic switch-off (Y/N)HR and BPchangeRate-pressure product at rest and stressAbnormal LGE (Y/N).Number of affected AHA segments (n)Pattern of abnormal LGE (ischaemic and non-ischaemic)Myocardial infarct scar burden Native T1 ECV Feature-tracking and DENSE (two methods)Longitudinal strain Circumferential strain Radial strain Present (Y/N)Clinically significant (Y/N)Sex, age and traditional CAD risk factorsCAD risk scores (JBS3 and ASSIGN)Gensini score of epicardial plaque burdenAssociation of myocardial perfusion with IMR, CFR, RRR and endothelial function testing (continuous and binary)Subset of patients with multivessel invasive coronary artery function measurementsAssociation with clinical diagnosis (ANOCA disease endotype)LV volumes and massMyocardial strainNative T1 relaxation time and ECVPresence of LGEDiagnostic accuracy of quantitative perfusion CMR to detect abnormal IMR, CFR, RRR and endothelial dysfunctionAHA, American Heart Association; ANOCA, angina with no obstructive coronary artery disease; BP, blood pressure; CFR, coronary flow reserve; CAD, coronary artery disease; CO, cardiac output; CorCMR, Coronary Microvascular Angina Cardiac MRI; EF, ejection fraction; EDV, end-diastolic volume; ESV, end-systolic volume; ECV, extracellular volume; HR, heart rate; IMR, index of microcirculatory resistance; LV, left ventricular; LGE, late gadolinium enhancement; MBF, myocardial blood flow; MPR, myocardial perfusion reserve; RRR, relative resistance ratio,The CorMicA trial has a comprehensive statistical analysis plan that governs all statistical aspects of the study authored by the trial statistician. The statistical analysis plan includes the prespecified CorCMR substudy that is designed to assess for associations between CMR measures and invasive measures and endotypes (reference dataset). Continuous outcomes will be analysed using linear regression with adjustment for baseline levels where available. Where continuous data are clearly not normally distributed, standard transformations will be applied to achieve approximate normality prior to analysis. Appropriate alternative regression methods will be applied to other types of data .The primary outcome is the proportion of patients with an MPR<2.0. The proportion of patients with microvascular angina defined by invasive endotyping will be assessed. We will further assess the MPR ratio with the highest AUC for microvascular angina classified invasively.Considering the correlation between CFR measured invasively and MPR measured non-invasively within the common territory of a major epicardial coronary artery, then a sample size of 110 subjects would enable a minimum clinically significant correlation of 0.3 to be detected with 90% power at a 5% significance level. If only 60 subjects have available data, then 80% power would be available to detect a correlation of 0.37 at the 5% level.The British Heart Foundation CorMicA trial will assess a routine stratified medicine strategy in a large cohort of prospectively enrolled patients with ANOCA. The prespecified CorCMR substudy will involve comprehensive invasive tests of coronary artery function paired with multiparametric perfusion CMR studies. The analysis will provide information on the diagnostic value of quantitative pixel-wise mapping of myocardial perfusion in this population.Contemporary guidelines recommend functional testing, including with CMR, to assess for myocardial ischaemia in patients in whom multidetector CT coronary angiography has shown CAD of uncertain functional significance or is non-diagnostic.The CorCMR substudy will be performed on a 1.5 Tesla MRI scanner. In comparison, 3.0 Tesla imaging permits improved signal-to-noise ratio and provides higher in-plane spatial resolution perfusion imaging.et alet alPatients with confirmed microvascular or vasospastic angina have a precise diagnosis of the underlying disease endotype, and pharmacotherapy may be commenced as appropriate. Conversely, patients with normal invasive coronary artery function tests may have antianginal therapy appropriately discontinued, and alternative causes of chest pain investigated. In comparison with invasive tests of coronary artery function, non-invasive CMR imaging may be more attractive to patients, but at present, the role of CMR in the diagnostic work-up of patients is uncertain. CorCMR will provide data on the role of CMR in the diagnosis of patients with ANOCA. Traditional non-invasive ischaemia testing in patients with ANOCA has provided mixed results. Panza et al compared semiquantitative perfusion CMR against IMR measurement in 50 patients with ANOCA and 20 age-matched healthy control subjects.et alCorCMR will inform the nascent evidence on the presence and magnitude of associations between invasive and non-invasive assessments of coronary vascular function. Liu et alCMR permits the reference-standard non-invasive assessment of myocardial tissue characterisation. CorCMR will provide data on diffuse interstitial fibrosis, ECV and myocardial scar. The role of T1 mapping and ECV analysis in patients with ANOCA is uncertain. In a substudy of the iPOWER natural history study, 54 women with ANOCA underwent native T1 mapping and ECV analysis, PET-derived MBF measurement, and transthoracic Doppler echocardiography CFR assessment.http://www.equator-network.org/reporting-guidelines/stard/) and Consolidated Standards of Reporting Trials (http://www.consort-statement.org/) guidelines.Progress in the trial will be monitored by the trial anager (KB) and sponsor. The study will be subject to internal and external audit that is routinely coordinated by the sponsor. An annual report will be submitted to the Research Ethics Committee on a 12-month basis. The flow diagram illustrates conservative estimates of patient enrolment and activity on a single site. The study will follow Standards for Reporting of Diagnostic Accuracy (STARD) (The CorCMR data will be presented at conferences and/or published in peer-reviewed journals.


Coarctation of aorta (CoA) is a discrete narrowing in aorta causing obstruction to the flow of blood. It accounts for 6–8% of all congenital heart diseases. With advances in fetal echocardiography rate of prenatal diagnosis of coarctation of aorta has improved but it still remains a challenging diagnosis to make prenatally. Transthoracic echocardiography is mainstay of making initial diagnosis and routine follow-up. Cardiac magnetic resonance imaging (MRI) and computed tomography (CT) are great advanced imaging tools for two-dimensional and three-dimensional imaging of aortic arch in complex cases. Based on type of coarctation, size of patient, severity of lesion, and associated abnormalities various management options like surgical treatment, transcatheter balloon angioplasty and transcatheter stent implantation are available. There is significant improvement in long-term survival from pre-surgical era to post-surgical era. But, among the postsurgical era patients, the long-term survival has not significantly changed between older and contemporary cohort. Patients with coarctation of aorta need lifelong follow-up event after successful initial intervention. Coarctation of aorta (CoA) can be simply defined as cardiac abnormality resulting in obstruction to the blood flow in the aorta. CoA can occur at any region in the thoracic and abdominal aorta. Most common location for CoA is just distal to the left subclavian artery at the point where ductus arteriosus connects to the aorta. Typically there is presence of medial thickening with “shelf like” tissue protruding in the lumen of aorta from the posterior aortic wall , 2. CoA EpidemiologyCongenital heart disease (CHD) accounts for nearly 28% of all major congenital anomalies . The birPathogenesisDuring embryonic period aorta develops from pharyngeal arches and its arterial system. Development of aortic arch starts in third week of gestation and the primordial pharyngeal arch arterial pattern is transformed into the final fetal arterial arrangement during eighth week of gestation. Ventral primitive aorta forms the aortic sac and dorsal primitive aorta forms the descending aorta. Developing pharyngeal arch arterial system connects these two portions. There are six sets of pharyngeal arches that contribute towards development of aortic arch and its branches. It should be noted that all the arches are not present at the same time during fetal period. Primary portion of the aortic arch develops from fourth pharyngeal arch and other arches contribute to development of branch pulmonary arteries, ductus arteriosus and aortic arch branches , 13. AnyThere are three leading developmental theories regarding formation of CoA. First, during development of aortic arch the tissue from ductus arteriosus may get incorporated in the aortic wall where it connects to the descending aorta. As the ductus arteriosus constricts after birth, this tissue in isthmus area constricts causing development of CoA , 14. SecClinical presentationThe clinical presentation and exam findings are variable based on patient’s age. Typically earlier presentation corresponds to severe disease.Younger ChildrenNewborns and neonates are usually asymptomatic right after birth as patent ductus arteriosus (PDA) helps perfuse lower body irrespective of severity of CoA. Neonates with severe/critical CoA develop signs and symptoms of cardiogenic shock as the ductus arteriosus closes after birth. Clinically, babies may show absent/feeble femoral pulse, delayed capillary refill, feeding problems, decreased responsiveness, metabolic acidosis, mesenteric ischemia, myocardial depression, etc. It is empirical to keep ductus arteriosus open with prostaglandin E1 infusion as soon as the diagnosis of severe/critical CoA is made and further definitive intervention can be performed. Beyond the neonatal period, cardiogenic shock is an unusual presentation but still a possibility during early infancy. Older pediatric patients are usually diagnosed due to weak femoral pulse, upper extremity hypertension, a systolic murmur over upper sternal border with radiation to the back, and upper-lower extremity systolic blood pressure gradient. Newborn pulse oximetry screening is a great tool in detecting cases of critical congenital heart disease in newborns. Although, its utility is limited in patients with pure CoA without presence of PDA (due to lack of mixing/shunting). Newborns with severe/critical coarctation with presence of PDA may have positive results on pulse oximetry screening due to right to left shunting at PDA .Adolescent and AdultsAlmost always these patients are diagnosed with CoA during workup of systemic hypertension or heart murmur. Clinical signs may include upper extremity hypertension, weak femoral pulse, arm-leg blood pressure gradient (>20 mmHg is significant), a systolic murmur on the back from flow through the coarctation segment or a continuous murmur from the collateral flow around the coarctation site. Patients may also complain of frequent headaches resulting from systemic hypertension and lower limb claudication from chronic hypoperfusion. If the collateral circulation around the coarctation site is significant then distal pulses may be adequate and arm-leg blood pressure gradient may not be significant.HypertensionSystolic hypertension improves and need for antihypertensive medications decreases in almost all patients after successful intervention, but chronic hypertension remains a significant issue in large proportion of patients with CoA. Prevalence of hypertension is lower in patients who are treated during neonatal period and infancy. Overall prevalence of long-term hypertension is noted at 25–68% . PreoperDiagnostic imagingTransthoracic echocardiography (TTE) is the preferred diagnostic modality for diagnosis and follow-up of CoA. Fetal echocardiography (FE) has advanced significantly over past couple of decades to allow us to make prenatal diagnosis of CoA and avoid cardiovascular catastrophe after birth. Cardiac MRI (cMRI) and cardiac computed tomography (CT) have emerged as a sophisticated second line of advanced imaging that provides excellent image resolution and anatomical details. Prior to advances in echocardiography, cardiac catheterization was the mainstay for making the diagnosis of CoA. In current era, it is primarily used for interventional purpose.Fetal EchocardiographyPrenatal diagnosis of CoA helps with parental counselling, delivery planning, avoids postnatal cardiac emergencies, and guides timely management . PrenataTransthoracic EchocardiographyTTE remains the mainstay of postnatal diagnosis and follow-up for aortic arch anomalies. Goal of TTE is to identify arch anatomy, site of coarctation, determine severity, and assess for associated intracardiac abnormalities , 25. SupTransesophageal EchocardiographyTransesophageal echocardiography is seldom used for primary diagnosis of CoA due to its invasive nature and limited views for arch imaging . It is uComputed TomographyCT angiography uses intravenous contrast and ionizing radiation to obtain intracardiac and extracardiac structural data with very high spatial resolution . CT alloMagnetic Resonance ImagingcMRI is a preferred non-invasive advanced imaging for patients with CoA . cMRI doElectrocardiogramElectrocardiogram is a typical initial screening test for heart rhythm evaluation and to assess for possible cardiac chamber enlargement. This can be normal or show evidence of left ventricular hypertrophy in patients with CoA. Newborns may show presence of right ventricular hypertrophy on electrocardiogram.Chest X-RayChest X-ray is helpful at looking for aortic arch sidedness on most patients. Classic “figure of three” sign can be seen on some patients with CoA. This is formed by patent pre-stenotic aortic nob, indentation from stenotic segment, and post-stenotic dilated segment. Patients with long standing unrepaired coarctation develop extensive collateral circulation through dilatation of intercostal arteries. These arteries run on the inferior aspect of the ribs. These patients can show inferior rib notching bilaterally from third to eighth ribs on chest X-ray .TreatmentSurgical repair, transcatheter balloon angioplasty and transcatheter stent implantation are treatment modalities available for management of CoA . Preferr- Non-invasive systolic blood pressure gradient of >20 mmHg between upper and lower limbs- Peak-to-peak transcatheter gradient of >/= 20 mmHg across the coarctation site- Peak-to-peak transcatheter gradient of <20 mmHg in the setting of extensive collateral circulation around the coarctation site- Significant left ventricular hypertrophy- Left ventricular systolic dysfunction- Uncontrolled systemic hypertension in the setting of coarctation of aorta- Abnormal blood pressure response during exercise stress testSurgerySince the first surgical repair of CoA in early 1940s by Dr. Crafoord, surgery remains a major treatment option for patients of all age group with CoA . In neonTranscatheter Balloon AngioplastyTranscatheter balloon angioplasty for native CoA was first introduced in the early 1980s . During Transcatheter Stent ImplantationTranscatheter stent implantation was introduced in the late 1980s and was widely accepted as a therapeutic measure for patients with CoA in the early 1990s . This isForbes et al. compared safety and efficacy of surgical and transcatheter treatment options for native coarctation at acute interval and at follow-up for patients between the years 2002 and 2009 from 36 institutions . They noCoA remains most common aortic arch abnormality in children. Key to optimum management of these patients is early detection and timely intervention. Various surgical and transcatheter options are available for management of CoA. Treatment option should be individualized for each patient based on associated factors. Lifelong follow-up is mandatory for these patients to monitor for any late complications.


Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Pseudomonas aeruginosa is known to tolerate antibiotic therapy during infection. This prevents clearance of infection and negatively impacts patient outcomes. Here, we report the transcriptome sequence of antibiotic-treated and untreated P. aeruginosa cultures and the differential gene expression observed when treated cells are compared to untreated cells. Pseudomonas aeruginosa is a Gram-negative bacterium which causes various human infections using a suite of virulence factors  reached 0.5, at which point the cells were collected and preserved in RNAprotect. Biofilms were formed in LB broth on borosilicate glass discs as described previously and preserved in RNAprotect (NC_002516) using Bowtie, allowing 2 mismatches in a default seed length of 28 nucleotides to prevent the mapping of low-quality reads  may be involved in antibiotic tolerance, these data will provide a starting point for investigating the mechanisms of tolerance in GSE120602.The RNA-seq reads and the DESeq results have been deposited in the NCBI Gene Expression Omnibus (GEO)  and are


Life on earth is sustained by oxygenic photosynthesis, a process that converts solar energy, carbon dioxide, and water into chemical energy and biomass. Sunlight is essential for growth and productivity of photosynthetic organisms. However, exposure to an excessive amount of light adversely affects fitness due to photooxidative damage to the photosynthetic machinery, primarily to the reaction center of the oxygen-evolving photosystem II (PSII). Photosynthetic organisms have evolved diverse photoprotective and adaptive strategies to avoid, alleviate, and repair PSII damage caused by high-irradiance or fluctuating light. Rapid and harmless dissipation of excess absorbed light within antenna as heat, which is measured by chlorophyll fluorescence as non-photochemical quenching (NPQ), constitutes one of the most efficient protective strategies. In parallel, an elaborate repair system represents another efficient strategy to maintain PSII reaction centers in active states. This article reviews both the reaction center-based strategy for robust repair of photodamaged PSII and the antenna-based strategy for swift control of PSII light-harvesting (NPQ). We discuss evolutionarily and mechanistically diverse strategies used by photosynthetic organisms to maintain PSII function for growth and productivity under static high-irradiance light or fluctuating light environments. Knowledge of mechanisms underlying PSII maintenance would facilitate bioengineering photosynthesis to enhance agricultural productivity and sustainability to feed a growing world population amidst climate change. Cyanobacteria, algae, and plants convert sunlight into chemical energy through photosynthesis to provide oxygen and food building blocks that are essential for most life forms on earth. Photosynthesis starts with capture of light by light-harvesting antenna, which drives photosynthetic electron flow through photosynthetic machinery comprising several large protein complexes embedded in the thylakoid membranes of prokaryotic cyanobacteria and eukaryotic chloroplasts. Oxygen-evolving photosystem II (PSII) is a highly conserved multi-subunit pigment-containing membrane complex that functions as a light-driven water:plastoquinone oxidoreductase during photosynthetic electron transport  LQY1 (LOW QUANTUM YIELD OF PHOTOSYSTEM II 1) protein—interacting with HHL1—regulates repair of damaged core complexes to sustain high PSII efficiency upon exposure to excessive light  and diatom Phaeodactylum tricornutum both need the LHCSR (LHC STRESS-RELATED PROTEIN) family protein for NPQ formation. Synthesis of the Chlamydomonas LHCSR protein is dramatically induced by high light, and it is responsible for the majority of flexible NPQ  protein in higher plants plays a similar role to the algal type LHCSR. It senses the pH of the chloroplast thylakoid lumen when there is excess light and induces flexible NPQ . Short-lin, LCNP . Intriguin, LCNP . These din, LCNP . The impin, LCNP .The wide distribution of NPQ across photosynthetic prokaryotes and eukaryotes highlights its crucial role in PSII photoprotection. Notably, different NPQ systems have evolved in these diverse photosynthetic organisms. Flexible NPQ (qE), the major and also best-studied component of photoprotective excess energy dissipation, constitutes three systems, which are classified based on their associations with the diversification of the light-harvesting equipment in photosynthetic organisms: the OCP (ORANGE CAROTENOID PROTEIN)-dependent system in cyanobacteria, the LHCSR-dependent system in algae and mosses, and the PsbS-dependent system in mosses and vascular plants . Therefolhcsr mutant  . Althougvia an ancient endosymbiotic event  protein is reported to have a crucial role in adjusting Arabidopsis photosynthesis to fluctuating light  and MET1 (MESOPHYLL-ENRICHED THYLAKOID PROTEIN 1) caused stunted phenotypes when exposed to fluctuating light intensities   is that NPQ relaxation lags behind fluctuations in sunlight during sudden transitions from high to low light. This happens when passing clouds or movement of neighboring leaves/plant species shade sunlit leaves. The slow NPQ response could cost up to 30% of carbon gain , suggestnditions . Much moIn oxygenic photosynthesis, it is important to (1) safely handle excess absorbed light energy that would otherwise cause massive ROS production and damage the photosynthetic machinery and (2) efficiently convert solar energy into chemical bond energy. Tight regulation of these two aspects may contribute to an increase in productivity in agriculture and natural ecosystems. Understanding the elaborate NPQ mechanisms and the robust PSII repair systems may help identify targets to optimize photosynthetic efficiency. This would facilitate translational work toward exploring yield potential to sustainably meet the global rising demands for food, fuel, and fiber in the future climate change. Prior to accomplishing these grand goals, multiple outstanding questions await to be addressed:Do antenna-based photoprotection and reaction center-based repair operate in concert or in parallel to regulate PSII efficiency and photosynthetic capacity under photoinhibitory light and other environmental stresses? How does evolution of NPQ in the oxygenic organisms contribute to that of repair and vice versa?How do ROS regulate PSII activity under fluctuating light environments or field conditions?Are the molecular mechanisms of PSII repair under changing light different or similar to those under high-light irradiance? Can photosynthetic species discern PSII damage caused by these two types of light conditions and initiate distinct repair strategies?JL and RL conceived the project. JL, YL, WH, and RL wrote and edited the manuscript.The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.


Alcohol-related problems affect increasing numbers of older adults. Recent studies have begun to investigate problem drinking among older adults based on a conceptual model proposing correlations between personal characteristics, life context , treatment, and drinking-related outcomes. In a community sample of older problem and nonproblem drinkers, alcohol consumption, life stressors, social resources, and coping responses differed between the two groups, although these factors did not directly and uniformly affect late-life drinking behavior. Furthermore, drinking behavior did not always have the expected effects on older drinkers’ life contexts. Findings from a sample of treated alcohol and other drug-abusing older patients demonstrated the importance of providing mental health aftercare for this group. Historically, most efforts to understand and treat problem drinkingThis heightened interest in the alcohol-related problems of older adults has inspired studies yielding considerable information about the scope and correlates of alcohol consumption and problem drinking in late adulthood. The current prevalence of alcohol abuse and dependence in the general population of older adults is between 2 and 4 percent; it is considerably higher—5 to 30 percent—in clinical populations . Most stRecent research highlights the importance of distinguishing between two groups of older problem drinkers: late onset and early onset. Late onset problem drinkers, of whom a significant proportion are women, first develop drinking problems later in life . Early onset problem drinkers, in contrast, develop drinking problems earlier during adolescence or adulthood and maintain them into late life. Compared with early onset problem drinkers, late onset problem drinkers generally are in better health , have better social relations , and are less likely to have been treated for alcohol and other drug (AOD) abuse , preventing inferences about the direction of causality between variables . Moreover, most studies have focused on correlations between personal characteristics  and late-life drinking behavior; few have considered the influence of the drinkers’ environmental contexts . Finally, little is known about either the factors that prompt older adults to seek help for their alcohol-related problems or the treatment efficacy for this group. This article presents a model for conceptualizing late-life drinking behavior. Based on this research model, the article also describes the findings of two long-term  research studies aimed at elucidating predictors of alcohol consumption, drinking problems, treatment seeking, and treatment outcome in older adults.The conceptual framework presented in The late-life drinking behavior model posits several relationships between these four domains :Both personal characteristics and life context affect treatment seeking as well as drinking behavior and outcomes.Drinking behavior, in turn, influences a person’s life context and certain personal characteristics.Some personal characteristics moderate the relationship between life context and outcomes.Treatment, including specific aspects of treatment programs, influences drinking-related outcomes.The validity of these assumptions was tested using a sample of older community residents as well as a sample of treated older AOD-abuse patients. The findings obtained with these two samples are described in the following sections.To examine the relationships between personal characteristics, life context, treatment seeking, and late-life drinking behavior, Brennan, Moos, and colleagues  studied Focusing on the latter two groups, the investigators addressed four questions: (1) Do the personal characteristics, life contexts, and coping responses of older problem drinkers differ from those of older nonproblem drinkers? (2) Do personal and life context factors at the beginning of the study predict drinking behavior 1 and 4 years later? (3) How does initial alcohol use in older problem drinkers affect their subsequent life context and psychological well-being? (4) What factors prompt older community residents to seek treatment for alcohol-related problems?Older problem and nonproblem drinkers differed with respect to several personal characteristics . As expeProblem drinkers also had more stressful life contexts than did nonproblem drinkers . Thus, tFinally, problem drinkers and nonproblem drinkers differed in their coping responses to stressful situations. Two broad categories of coping responses are approach coping and avoidance coping. Approach coping involves attempts to master or resolve a stressful situation; avoidance coping consists of efforts to avoid thinking about a stressor and its implications and includes the expression of stress-related emotions without attempting a resolution. A comparison of older problem and nonproblem drinkers showed that although both groups used comparable levels of approach-coping strategies to manage stressors, problem drinkers were more likely to use avoidance-coping strategies  Moos et.Consistent with earlier research  several Overall, these results implied that experiencing more stressors, having fewer social resources, and relying more heavily on avoidance coping could lead to late-life drinking problems. The results also suggested that drinking problems might harm the life contexts and psychological well-being of older adults. To learn more about these causal relationships, the participants were reassessed over extended periods of time.reduced alcohol consumption over intervals ranging from 1 to 10 years  tends to determine how social resources influence drinking behavior . Thus, iThe study’s findings also illustrate the influence of an older person’s drinking history on the relationship between life context and drinking behavior: The more alcohol the older drinkers consumed at the beginning of the study, the more likely were certain stressful life events, such as a relative’s sickness or injury, to cause an increase or a smaller-than-expected decrease in alcohol consumption at followup . SimilarThe use of certain coping responses also appears to moderate the effects of life context on late-life drinking behavior. For instance, more non-health-related negative life events predicted elevated drinking problems among older drinkers who relied heavily on avoidance coping. In contrast, among drinkers who used fewer avoidance-coping strategies, negative life events prompted a decline in drinking problems . SimilarTaken together, these observations belie the idea that life context directly and uniformly affects drinking behavior in later life. Whether and how stressors and social resources influence late-life drinking appear to depend on several factors, including (1) the specific type of stressors , (2) the type of drinking behavior being assessed , and (3) personal risk factors .Although several studies have analyzed the effects of life context on late-life drinking, few have considered the effects of older adults’ drinking behavior on their subsequent life contexts and personal well-being. Contrary to intuitive expectations, these studies indicate that ongoing drinking problems generally do not adversely affect the life contexts of older drinkers. For example, at the 1-year followup in the community study of older adults, problem-drinking women experienced a decline in spouse stressors, and problem-drinking men reported a reduction in conflicts with friends . MoreoveSimilarly, older adults’ drinking behavior affected their psychological well-being in unexpected ways. For example, heavier initial alcohol consumption among women predicted fewer subsequent depressive symptoms; among men, more initial drinking problems predicted reduced depression .Finally, one would expect remission from drinking problems to improve the life contexts of older men and women. However, remission had little influence on the life contexts of male problem drinkers. Moreover, women who remitted experienced a loss of support from extended family members and reported more family stressors at followup than did remitted men . Thus, fLonger term followups are needed to determine the permanence of these effects as well as their consequences. For example, do ongoing drinking problems eventually lead to increased interpersonal stressors? And do adverse family contexts or self-medication with alcohol to avoid depression pose relapse risks for older, remitted women? The answers to these questions might have treatment implications; older women in early remission, for example, may need enhanced support to cope with family conflict and depressive symptoms.Older adults rarely seek formal treatment . ConsistSeveral factors predicted whether these community residents sought treatment. The most important predictors were prior treatment seeking and a greater number of health problems compared with the rest of the group. Frequently using avoidance-coping responses, experiencing more negative life events, and having fewer friends who approved of drinking also predicted more treatment seeking . FinallyThese findings suggest that older adults in the community are reluctant to identify themselves as having drinking problems and therefore delay treatment until their health problems and stressful life contexts require it. This result highlights the importance of identifying and treating older adults’ drinking problems early. In addition, more information is needed about the personal characteristics, life contexts, and treatment features that deter older adults from seeking help for alcohol-related problems.Despite their reluctance to seek treatment, older adults constitute at least 20 percent of the AOD-abuse population in inpatient settings . Yet litBased on this information, the researchers addressed two broad sets of questions: (1) What are the extent and the predictors of health service use by older AOD-abuse patients? (2) To what extent is AOD-abuse treatment effective for older patients, and which specific treatment program characteristics predict better outcome?The VA AOD-abuse patients used health care services heavily. They received more than 920,000 days of care for AOD abuse or psychiatric disorders in the 4 years before their index episodes of care as well as 1.2 million days of care in the 4 years afterwards b. MoreovOlder and younger AOD-abuse patients received different types of treatment. Compared with younger patients, older patients received care focused more on their medical needs  than on their AOD-abuse and psychiatric treatment needs . MoreoveThe readmission rates of older patients depended in part on their AOD-abuse histories. First-time AOD-abuse patients had lower readmission rates than the total sample b. This fCo-occurring psychiatric disorders also affected the frequency of health service use and complicated the treatment of older AOD abusers. At the index episode of care, almost 30 percent of the patients suffered from concomitant psychiatric disorders, most commonly depressive disorders, personality disorders, and schizophrenia . These dIn addition to AOD-abuse history and the presence of psychiatric disorders, the study identified several other predictors of higher readmission rates for older AOD-abuse patients at both the 1- and 4-year followups. These predictors included being unmarried, more prior service use, more severe and complex psychiatric diagnoses, disrupted or shorter length of treatment, and insufficient mental health aftercare b, 1995.The question of treatment effectiveness among older AOD-abuse patients usually is framed as a comparison: Do older patients respond as well to AOD-abuse treatment as younger patients do? No definitive answer exists for this question (for reviews, see Some recent investigations have begun to clarify this issue by examining the match between age and specific treatment modalities. For example, Although the studies reviewed here have contributed new data about late-life drinking behavior, many questions remain. For example, further information is needed on the relationships between life context and drinking behavior in later life. Moreover, longitudinal studies should investigate the predictors of late onset problem drinking and its remission. Researchers must identify factors that deter older adults from seeking assistance for their alcohol-related problems and devise new screening and referral methods that facilitate earlier recognition and treatment of late-life drinking problems.The study of VA patients has demonstrated that older, treated AOD-abuse patients—especially those with long histories of alcohol abuse and psychiatric comorbidity—place a heavy burden on the health care system. Consequently, researchers and other professionals must work to evaluate and improve the treatment effectiveness in this patient population. Factors such as continuity of care and followup mental health care appear to promote better outcomes among older patients and may be especially important for patients who have fewer informal social resources from which to draw. Accordingly, researchers must determine how much and what kind of mental health aftercare is optimal for maintaining successful treatment outcomes among older patients.Future research also should address the match between the treatment needs of older AOD-abuse patients and particular treatment program characteristics. Currently, the data more clearly indicate which treatment approaches do not work well for older patients than which ones do. More broadly, a need exists for further theory development in the study of late-life drinking behavior and for more longitudinal investigations of older adults’ drinking behavior, especially among understudied populations, such as older women and older adults in racial minority groups. Such work should enhance our understanding of the course and predictors of late-life drinking behavior and assist clinicians in treating older adults’ alcohol-related problems.


Background: Given findings that generally support the benefits of information and communication technology (ICT) for older adults’ psychosocial adjustment, one might surmise that lonely older adults, who have a stronger need for psychological support, would reap more psychosocial benefits from ICT use. However, scant research has examined this view, much less the likelihood that ICT use might worsen the psychological well-being of lonely older adults, as has been shown to be the case in younger adults. Objective: To examine whether the association between ICT use and psychological adjustment  among older adults depends on their loneliness levels. Methods: A representative sample of 738 Hong Kong SAR Chinese older adults aged 60 years or older  was interviewed in 2017 on loneliness, frequency of ICT use , psychological distress , and SOC. Results: Regression analyses showed that loneliness significantly moderated the relationship between ICT use frequency and psychological adjustment ; more frequent ICT use was associated with more psychological distress and less SOC, with higher levels of loneliness. Conclusion: These findings suggest that ICT use may be a mixed blessing for older adults, i.e., using more ICT might predict worse psychological adjustment among lonelier older adults. Efforts that promote ICT use among older adults should take their loneliness levels into account.


Early recognition of VATS-related complications is crucial for early interventions, treatments and better outcomesPatient presented with post-obstructive pneumonia like symptoms 1 week after VATS pulmonary resection.CT scan chest showed evidence of complete consolidation of the lobe where the pulmonary segmentectomy resection took place.Diagnostic bronchoscopy confirmed the erroneous transection of the Superior Segment (SS) of Right Lower Lobe (RLL). Patient was then taken back for completion lobectomy and found with necrotic SS of RLL. This finding potentially could have caused significant complication if not recognized and treated earlyPatient recovered well after completion lobectomy and was discharged home several days laterErroneous bronchial transection should be suspected early in patients presenting with post-obstructive pneumonia after VATS pulmonary resection. CT scan chest and diagnostic bronchoscopy are the 2 main diagnostic tests This minimally invasive approach is currently employed for diagnostic and therapeutic lung surgery, as well as other procedures involving the mediastinum, chest wall, pericardium, esophagus and diaphragm. In general, VATS procedures are well tolerated and the prevalence of major intraoperative complications is around 1.5%.2We present a 65 year old woman, with a history of prior left upper lobectomy for early stage non-small cell lung cancer, who underwent elective VATS for a highly suspicious right lower lobe lung nodule Fig. . The nod3In this case, diagnostic bronchoscopy led to an early recognition of erroneous bronchial transection which ultimately was treated with completion lobectomy and saved this patient significant morbidity. Had the bronchoscopy not been performed, her clinical and radiographic findings would have been blamed on severe pneumonia and broad-spectrum antibiotics would have been administered hoping for clinical improvement.–5 In all cases, the fissure-last technique has been identified as a potential cause of this complication. In this technique, the surgeon dissects and transects the hilar structure first then proceeds to complete the fissure with a stapling device last.,7 The fissure-last lobectomy requires advanced expertise and recognition of anatomical structures prior to attempting transection of the hilar structures. A ventilation test after clamping the targeted bronchus could also be helpful. The fissure-last technique could be challenging especially in right-lower lobectomy and when a ventilation test is neglected or not performed.,7The erroneous bronchial transection has been reported as a major complication of VATS pulmonary resection ranging from 0.9 to 1.8%.Just like in this case, the evaluation of pneumonia early after VATS lung surgery should include a CT scan of the chest. Careful review of the operative report, identification and visualization of ipsilateral remaining proximal airways, and localization of surgical clips on imaging are crucial in diagnosing an erroneous bronchial transection of remaining neighboring lobes or segments to the resected part of the lung. If the CT scan shows an unexplained complete consolidation of any lobe or segment and bronchus cut-off sign with presence of proximal surgical clips, a diagnostic bronchoscopy is warranted with careful examination of the airways looking for erroneous transection. Discussion with the surgical team and aggressive surgical resection of the affected segment or lobe are the mainstay of treatment approach.In summary, in patients presenting early after VATS pulmonary resection with signs and symptoms of pneumonia, CT scan chest with careful focus on airway patency is an important diagnostic test. Suspicious findings should be futher investigated with a diagnostic bronchoscopy to rule out an erroneous bronchial transection followed with surgical intervention if applicablePatient has provided informed consent for publication of the case and accompanying imagesWriting – original draft: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib.Writing – review & editing: Amit Borah, Steven Cocciardi, Ziad Boujaoude, Wissam Abouzgheib.


This study examined the trajectories of pain, insomnia, and depression during a four-year period in community-dwelling participants aged 65 or older  from the National Health and Aging Trends Study. Self-reported pain, insomnia, and depressive symptoms were collected at each wave. Dementia status was determined using a modified previously validated algorithm. We analyzed retrospective trajectories of each symptom using mix-effect models and a backward timescale. We also tested for differences in each symptom trajectory between those with and without dementia. Results showed that the trajectory of depression significantly differed by dementia status . Participants with dementia had persistently higher depression level than those without dementia, particularly during the year before dementia onset. Trajectories of pain and insomnia did not differ before dementia onset. Depression increases risks of dementia and studies with longer length of follow-up are needed to detect significant trajectories of pain and insomnia before dementia onset.


Retroviruses have invaded vertebrate hosts for millions of years and left an extensive endogenous retrovirus (ERV) record in the host genomes, which provides a remarkable source for an evolutionary perspective on retrovirus-host associations. Here we identified ERV variation across whole-genomes from two chicken lines, derived from a common founder population subjected to 50 years of bi-directional selection on body weight, and a distantly related domestic chicken line as a comparison outgroup. Candidate ERV loci, where at least one of the chicken lines indicated distinct differences, were analyzed for adjacent host genomic landscapes, selective sweeps, and compared by sequence associations to reference assembly ERVs in phylogenetic analyses. Current data does not support selection acting on specific ERV loci in the domestic chicken lines, as determined by presence inside selective sweeps or composition of adjacent host genes. The varying ERV records among the domestic chicken lines associated broadly across the assembly ERV phylogeny, indicating that the observed insertion differences result from pre-existing and segregating ERV loci in the host populations. Thus, data suggest that the observed differences between the host lineages are best explained by substantial standing ERV variation within host populations, and indicates that even truncated, presumably old, ERVs have not yet become fixed in the host population. Retroviruses have infiltrated vertebrate germline for millions of years by integrating as proviruses in host DNA, which have then passed down to the offspring through generations as inherited endogenous retroviruses (ERVs). The genomic ERV record represents retroviruses that were replicating at the time of integration and constitutes large fractions of contemporary vertebrate genomes, for example about 7–8% of human DNA ,2 and abgag, pol, and env genes [Diverse sets of ERVs can be identified across all studied vertebrate genome assemblies  by screenv genes . Over tinv genes . ERV connv genes , modificnv genes ,7. On thnv genes ,8,9. ERVnv genes ,11,12,13It is desirable to identify orthologous ERV loci across the compared host lineages in order to evaluate potential effects of retroviruses and ERVs on host biology because it allows for connecting ERV integrations to host phenotypic differences and evolutionary history. ERV studies have benefited from recent advancements in sequencing technology and a growing catalogue of reference host genome assemblies, where much focus has been placed on comparing ERV records across related host species reference genome assemblies, an approach that suffers from undersampling of the diversity within vertebrate species, and thus presents challenges for reaching a better understanding of potential factors that contribute to the long-term retrovirus-host associations . More reIn an attempt to further explore ERV-host associations in a hitherto un-examined system, we make use of an artificial selection system where selection lines of domestic chicken that have been undergoing strong bi-directional selection on body weight at eight weeks of age for more than 50 years . This seDomestic animals provide rare possibilities, currently not feasible in human biomedicine, to study connections between genes, phenotypes, and biological function . CrossbrThe rationale for utilizing chicken as a model dates back more than 100 years to pioneering studies of retroviruses and ERVs, reviewed in ,20, and Here, we identify ERV insertion differences across available re-sequenced genomes derived from the two bi-directionally growth-selected chicken lines and compare candidate ERV loci with a commercial layer chicken outgroup. We map insertions and deletions to establish their positions relative to the adjacent host genomic landscape and compare candidate loci associated by sequence similarity to ERVs identified in the Red junglefowl reference assembly  along with reference retroviral sequences within a phylogenetic framework.http://genome.ucsc.edu) by Rubin et al. [Whole-genome re-sequenced DNA from domestic chicken selection lines was analyzed for differences in ERV makeups as potential markers for effects of ERVs on host genome function and evolution, see n et al. .Briefly, to allow identification of reference as well as non-reference assembly ERVs using mate-pair short reads sequencing technology, we applied a strategy where reads were mapped to an independent ERV library and then located along host chromosomes by anchoring their mate-pair reads to positions in the flanking host DNA. The RetroTector software  was usedp < 4 × 10−6) after Bonferroni correction for multiple testing.Candidate ERV loci were tested for read mapping differences across the re-sequenced chicken lines  using Fisher’s exact test if the minimum observed read counts at the locus were fewer than 15 and otherwise by comparison to the Chi distribution. Loci where short reads were missing in one or two of the three chicken lines were kept for further analyses if p-values for ERV-associated read counts passed the conservative threshold (http://genome.ucsc.edu) and intersected with positions for candidate ERV loci in order to explore biological significance of genes located adjacent to ERVs and their potential associations with the chicken selection line phenotypes. Associations among chromosomal genes and ERVs, intragenic as well as intergenic positions covering 150 kb up- and downstream of reference gene transcription start sites were analyzed. Candidate ERV loci were intersected with sweep regions previously determined for the H and L chicken selection lines [https://david.ncifcrf.gov/) to explore biological impact of differences in ERV integrations across the H and L chicken selection lines.The Red junglefowl  reference gene dataset was downloaded from the UCSC genome browser , and visualized using FigTree v1.4.2 (http://tree.bio.ed.ac.uk/software/figtree/).Phylogenetic analyses of ERVs identified in the reference assembly  together with reference retrovirus sequences were performed as previously described ,25,26. BastTree2 . The resWhole-genomes from domestic High-Growth (H), Low-Growth (L), and White Leghorn (W) chicken selection lines were previously sequenced using high throughput SOLiD technology and mapped to the chicken reference assembly  by Rubin et al. , see TabGallus gallus, which was separated from the investigated chicken lines about 8000 years ago when chicken was first domesticated, see The bi-directionally growth-selected chicken lines (H and L) diverged from a single broiler founder population about 60 years ago and were separated more than 100 years ago from the branch leading to the comparison outgroup represented here by the commercial White Leghorn (layer) chicken. For reference, the compared chicken lines share a relatively recent common ancestry, compared to the reference genome assembly, generated from the Red junglefowl, http://genome.ucsc.edu) and previously determined selective sweeps for the H and L chicken selection lines [p = 0.1, binomial test), given the size of the sweep areas and the number of detected ERV insertions elsewhere in the host genomes. In addition, gene ontology searches were inconclusive and could not establish links between ERVs and adjacent host genes that could help explain the distinct phenotypes. We, therefore, analyzed candidate ERV insertion orientations and distances relative to host genes. Candidate ERV loci within host gene transcripts show a clear bias in antisense orientation relative to the host gene transcript, which could be explained by purifying selection due to potential splice interference from canonical splice signals as previously discussed [To explore potential connections between the observed divergent ERV loci across the domestic chicken lines, we intersected chromosomal positions with the reference assembly host genes , divergent ERV loci in the domestic H, L, and W chicken lines located across the phylogenetic tree that was rooted on a distant outgroup, rather than being found inside any specific retroviral clade, which is what could be expected if variation was due to retroviral expansion after the last common ancestor. Instead, the result indicates that the observed candidate ERV insertion differences do not result from recent retrovirus replication and integrations as ERVs in one or two of the chicken lineages, but rather it is consistent with standing variation of segregating ERV loci present at the onset of the bi-directional selection experiment as well as during breed formation since the domestication of chicken. Multiple radiations involving candidate ERV loci associated with assembly ERVs showing short terminal branch lengths indicate relatively recent expansions occurring within several retroviral genera across the phylogeny. It seems plausible that these radiations have generated a substantial number of segregating ERV insertions in the domestic chicken lines, thus providing the standing variation that explains the observed differences in ERV makeups, and that the number of divergent ERV loci is largely a product of the accelerated genomic divergence caused by the strong selection imposed on the H and L lines specifically, as well as directed selection of host features during domestication, which has affected all three studied  chicken lines.The known breeding history and well-studied phenotypic traits among domestic animals make them first-rate model organisms to identify potential ERV contributions to biological functions and dynamics of complex genetic traits. Rare genomic changes resulting in host phenotypes that would require thousands of years to establish, or become lost, in wild host populations may be selected for in domestic settings during fewer generations ,21,29. THere, we utilized whole-genome sequences from two bi-directionally growth-selected domestic broiler chicken lines and a distantly related domestic layer chicken line  for idenAs high-throughput parallel sequencing technologies generate short reads and limited coverage into the ERV loci depending on mate-pair insert sizes for reliable chromosomal anchoring, we utilized ERVs identified in the Red junglefowl reference assembly to generate an independent ERV search library and anchored loci to chromosomal positions by ERV-associated short reads mate-pair mapping. Despite limited ERV sequence coverage, it is thus possible to associate the best fit for candidate ERV loci reads with assembly ERV sequences, which could be used to construct phylogenetic frameworks and to determine associations between ERV loci and host genomic landscapes.The whole-genome sequences were generated from pooled individual DNA, see However, although gene ontology searches for genes adjacent to divergent candidate ERV loci could not explain host phenotypic variation, which could be due to the known highly polygenic nature of the trait under selection ,29, inteSimilar observations have also recently been made in other vertebrate host populations , demonstWhile it can be informative to study ERV variation from host species assemblies covering multiple species over long evolutionary time scales ,25, analIn summary, it appears increasingly important to employ careful experimental design to control the occurrence of artifacts and incorrect inferences due to unbalanced sampling in analyses aimed at evaluating host species ERV makeups. In order to obtain valid comparisons from population and distantly related genomes, it is valuable to focus on well-known pedigrees like those offered by domestic animal selection lines, where the prior knowledge makes it possible to compare observed patterns with expectations that are based on the evolutionary context of the specific case with higher precision than is generally achievable in natural populations. Sequencing and analyses of domestic animal populations and single genomes from known selection pedigrees facilitated by improved sequencing technologies that provide depth and coverage over long insertion sizes together with newly developed and fine-tuned analysis methods will facilitate mapping of ERVs previously not feasible and thereby generate new knowledge about contributions from retroviruses and ERVs to host genome function and evolution.


The literature is mixed with respect to how stress reactivity changes with age. Previous studies have overlooked contexts, ignoring whether stressors occurred in the laboratory or in daily life. The Health and Daily Experiences (HEADE) study includes 126 younger and older adults who completed both laboratory stressors and ecological momentary assessments (EMA) of affect and stressor experiences in daily life. We found that the laboratory stressor elicited the greatest levels of negative affect reactivity  and positive affect reactivity  compared to the two types of daily life stressors. Interpersonal stressors were associated with greater negative and positive affect reactivity compared to non-interpersonal stressors in daily life. Younger adults exhibited greater stress reactivity than older adults. Together, these findings support age-related reductions in stress reactivity. Implications for understanding stressor-health links are discussed.