The SmartPrompt phone-based reminder application was designed according to neuropsychological theory and pilot testing to facilitate everyday functioning. A laboratory-based pilot of ten participants with MCI and mild dementia showed significantly greater task completion with significantly fewer checking behaviors when using the SmartPrompt versus a control condition. Younger individuals and those who engaged in more checking behaviors completed more tasks in the control condition, but these relations were not significant when using the SmartPrompt. After 15 minutes of training, caregivers achieved near perfect scores on a SmartPrompt configuration quiz. Participant and caregiver usability ratings were strong, even though participants reported relatively low computer proficiency and neutral/unfavorable attitudes towards technology. Piloting informed modifications of the SmartPrompt to enhance personalization  and improved human-computer-interaction for in-home testing. Preliminary in-home test data on individually-owned smartphones and conclusions regarding barriers and facilitators to the effectiveness of the modified SmartPrompt will be discussed.


Dear Editor:Autosomal Dominant Polycystic Kidney Disease (ADPKD) is the most common inherited kidney disorder and affects up to 12 million individuals worldwide. Radiologic imaging is critical for successful management. Until recently, the treatments were only symptomatic but EMA in 2017 and FDA in 2018 approved Tolvaptan for ADPKD therapy. Renal imaging provide important diagnostic and management guidance in the monitoring of disease progression. In the past, standard radiographic imaging has not provided the accuracy necessary to reliably measure renal volume. With diagnostic advances, kidney volume growth is considered the principal surrogate marker predicting the decline of renal function in ADPKD; therefore the role of total kidney volume (TKV) has been investigated as surrogate endpoint in randomized clinical trials. TKV can be measured by ultrasonography (US), computed tomography (CT) and magnetic resonance imaging (MRI) using manual, semiautomated, or fully automated data processing techniques.Using high-resolution MRI, the Consortium of Radiologic Imaging Studies of PKD (CRISP), observational cohort study of ADPKD subjects, investigated the ADPKD progression highlighting that MRI could accurately and reliably measure TKV cystic kidneys.


This paper explored the effect of the type of health insurance on dentist visits among older adults in China. The data were drawn from the CHARLS-II (2013). The sample included older adults aged 60 and older =3272, n=3495). Multivariate logistic regression models indicated that in urban and rural places, respondents with a governmental/civil servants’ insurance and those with an urban-employee insurance are more likely to visit a dentist in the survey year. Household registration status (hukou) does not play a significant role in dentist visits when insurance types are adjusted for. In other words, employment status, and the coverage of health insurance presented more significant effects on dentist visits. Differing from previous studies about urban-rural health disparities, this study disclosed substantial institutional influences on dental care access among older adults.


Pulmonary vein stenosis or occlusion is a rare but one of the most devastating complications after catheter ablation for cardiac arrhythmias, and surgical repair is an option in severe cases. The sutureless technique, which avoids direct suture of vessel walls, was initially described for congenital pulmonary vein stenosis and has been widely performed due to its good restenosis-free rate.A 52-year-old male developed left pulmonary vein occlusion after catheter ablation for atrial fibrillation. The surgical repair with sutureless technique using the left atrial appendage was performed without any complications. Postoperative computed tomography demonstrated the revascularization of the pulmonary vein.The sutureless technique using the left atrial appendage is significantly reasonable particularly in case of left pulmonary vein stenosis or occlusion after catheter ablation for atrial fibrillation since it reduces the risks of restenosis and thromboembolism. Pulmonary vein (PV) stenosis occurs as a complication of catheter ablation for cardiac arrhythmia in 1–3% of patients [A 52-year-old male with AF underwent catheter ablation for two times. Eight months after the second maneuver for recurring AF, he presented with hemoptysis and exertional dyspnea. Computed tomography (CT) showed multiple consolidation in the left lung and ipsilateral pleural effusion Fig. . Three-dPV stenosis often develops as a congenital anatomical anomaly or anastomotic stenosis occurring after the repair of total anomalous PV connection, and several surgical repairs including endovenectomy, re-implantation of PV with direct anastomosis, or patchplasty have been described , 3. HoweThe sutureless technique using the LAA for the left PV stenosis or occlusion after catheter ablation for AF is a significantly reasonable procedure in terms of reducing the risks of restenosis and thromboembolism. Since the long-term outcome of this technique is still unknown, careful follow-up is required.


Empathy for pain is a complex phenomenon incorporating sensory, cognitive and affective processes. Functional neuroimaging studies indicate a rich network of brain activations for empathic processing. However, previous research focused on core activations in bilateral anterior insula (AI) and anterior cingulate/anterior midcingulate cortex (ACC/aMCC) which are also typically present during nociceptive (pain) processing. Theoretical understanding of empathy would benefit from empirical investigation of shared and contrasting brain activations for empathic and nociceptive processing.Thirty-nine empathy for observed pain studies  were selected by systematic review. Coordinate based meta-analysis (activation likelihood estimation) was performed and novel contrast analyses compared neurobiological processing of empathy with a comprehensive meta-analysis of 180 studies of nociceptive processing (Conjunction analysis indicated overlapping activations for empathy and nociception in AI, aMCC, somatosensory and inferior frontal regions. Contrast analysis revealed increased likelihood of activation for empathy, relative to nociception, in bilateral supramarginal, inferior frontal and occipitotemporal regions. Nociception preferentially activated bilateral posterior insula, somatosensory cortex and aMCC.Our findings support the likelihood of shared and distinct neural networks for empathic, relative to nociceptive, processing. This offers succinct empirical support for recent tiered or modular theoretical accounts of empathy. Empathy is a critical concept in human emotional and social experience. The ability to share in the affective states of those around us brings evolutionary advantages, enabling us to respond to the needs of others, predict their behaviour and support decision-making about our own actions  and sociNociceptive (pain) processing is associated with wide-reaching patterns of neural activation which briefly encompass bilateral anterior, mid-and-posterior insula cortices, primary and secondary somatosensory cortex, inferior frontal gyri (IFG) and supramarginal gyri, as well as medial clusters in anterior cingulate/anterior midcingulate cortices (ACC/aMCC), thalami and brainstem .The Perception–Action Model (PAM) of empathy , suggestHowever, current definitions of empathy suggest the involvement of automatic affective processing but also include aspects of higher order cognition. For example, empathy requires isomorphic sharing of feelings with another, but also necessitates awareness that one’s state originates from observation of the target . In suppThe Russian-Doll model of empathy posits a tiered system with progressive levels of empathy from basic affective  to higher order processes such as sympathetic concern and emotional perspective taking . SimilarNeuroimaging studies demonstrate a heterogeneous profile of activation foci for empathy for pain , as were supplementary and manual searches. Both authors were responsible for assessment of articles for inclusion, and decisions over article inclusion were determined by discussion, disagreements where resolved via discussion or presented to a third arbiter (A.S.). One author (N.F.) extracted the relevant coordinate data, which was cross-checked and confirmed by a second (C.R.). Studies that reported coordinates in the Talairach space were converted into MNI using GingerALE software for the purposes of analysis and reporting.P < 0.001 uncorrected voxelwise throughout the whole brain with at least P < 0.05 cluster level correction  declared. We excluded papers which only reported ROI results.The criteria for inclusion were: (i) human fMRI studies published up until October 2019; (ii) original English language articles; (iii) published in a peer-reviewed journal; (iv) utilizing a paradigm including visual pain stimuli i.e. images, videos or animations of pain scenes or pain facial expressions; (v) employed an appropriate contrast with a suitable control stimulus ; (vi) coordinates were reported in the paper or supplementary material of the direct (pain > non-pain) contrast in either Montreal Neurological Institute  was implemented followed by cluster-level Family-wise error (FWE) correction (P < 0.05) to identify relevant ALE regions as recommended in recent publications (P < 0.05) and a minimum cluster size of 200 mm3 as previously recommended  middle frontal gyrus, and bilateral supramarginal regions .Contrast analysis comparing the ALE maps of concordant activations for each process pointed to significantly greater likelihood of activation during empathy for pain relative to directly perceived pain in 6 clusters encompassing bilateral supramarginal, IFG and occipitotemporal regions .The reverse contrast revealed six clusters indicative of increased activation likelihood estimates for directly perceived pain relative to empathy for observed pain. These regions encompassed two large bilateral clusters encompassing parietal opercular cortices (S2), posterior insula and S1. Right putamen was also evident for directly perceived pain relative to empathy. A right frontal cluster encompassing right prefrontal and dorsolateral prefrontal cortices was also elicited. Two medial clusters demonstrated increased concordance of activation in direct, relative observed, pain in aMCC .The findings of the ALE meta-analysis of empathy for pain revealed concordant activations to observed pain stimuli located in aMCC and bilateral AI which accords with previous investigations  were also performed for the first time. Empathy, compared to direct pain experience, demonstrated preferential bilateral activation in supramarginal regions, which extended superiorly to the supramarginal gyrus. Although supramarginal activations are frequently reported in fMRI empathy literature, their specific relevance is often not subject to discussion or interpretation, particularly if the basic empathy contrast is not the primary aim of the research . This poContrast analyses also pointed to bilateral occiptotemporal activations that were more likely to be engaged during observed pain, but not direct pain experience. Previous fMRI research have explained these activations for empathic viewing in terms of enhanced visual processing  or attenContrast analyses also revealed greater bilateral activation in ventral IFG during empathy for pain relative to direct experience of pain. The IFG is frequently activated during motor imagery or action observation type paradigms , it has ALE of directly perceived pain, compared to empathy, demonstrated preferential concordance of activation in bilateral S1, posterior insula and parietal operculum, right putamen, right prefrontal cortices and aMCC. Posterior insula and parietal opercular cortices represent the primary targets of nociceptors in the spinothalamic tract  and the From a theoretical perspective, the patterns of ALE seen in conjunction and contrast analyses show alignment with a tiered theoretical understanding of empathic processing such as the Russian-Doll model  or indepThe role of inferior parietal and occipitotemporal cortices for a broad range of social processing is a topic of considerable research, and a nexus of social processing extending from the angular gyrus of the TPJ anteriorly to supramarginal gyrus and posteriorly to occipitotemporal cortices was posited . Others The present study has some limitations. As mentioned, we focused on empathy for observed pain rather than more complex iterations of cognitive empathy such as paradigms which utilize learning to associate abstract cues with pain stimulation delivered to another person located outside of the scanner. The former design is more prevalent in fMRI research , allowinTo surmise the impact of the present study, elucidation of a rich functional brain network of empathy for pain, extending beyond AI and aMCC, is important for theoretical understanding of the phenomenon. The conjunction and contrast analyses reveal, for the first time, shared and distinct networks for observed and direct pain which supports the concept of tiered levels of processing of empathy as were previously theorized . The finTo conclude, the findings reveal concordance in an extensive bilateral network of brain regions for empathy for observed pain. This encompassed bilateral AI, supramarginal gyri, lateral occipitotemporal cortices IFG and aMCC, regions with functional relevance for interoception, pain processing, social cognition and self-other distinction. Utilizing novel contrast analyses for empathy for pain and direct pain experience, we demonstrated a broad network of shared brain representations which align to automaticity of response or emotional contagion, and empathy-specific activation patterns with relevance for higher order responses such as self-other distinction. Knowledge of these shared and distinct brain networks offers a novel insight into the neurobiological underpinnings of our subjective experience of empathy with relevance for theoretical, clinical and social applications.None declared.File013_nsaa090Click here for additional data file.


Introduction: Cardiovascular diseases (CVDs) remain the leading cause of morbidity and mortality in the United States. Preexisting chronic health conditions may be confer increased CVD risk, specifically fibromyalgia (FM), a chronic condition characterized by widespread pain, fatigue, stiffness, and concentration problems. CVD risk increases with normal aging; however, characteristics of FM are suggested to exacerbate health profiles in normal aging processes that may contribute to increased CVD risk. Method: The sample included 221 older adults  and 55% reported an FM diagnosis. CVD risk factors were entered separately in a five-block hierarchical binary logistic regression model as predictors and included: cardiorespiratory fitness using the six-minute walk, BMI, standing and lying mean arterial pressure (MAP), and depression using the Beck Depression Inventory. Results: Logistic regression analyses revealed that poorer cardiorespiratory fitness , greater depressive symptoms  and lower standing MAP  were associated with higher odds of an FM diagnosis. However, no differences in lying MAP  or BMI  for an FM diagnosis emerged. Discussion: These data support the importance of examining the health profiles of persons with FM in the context of CVD risk. Experiences of FM may produce distinct health profiles with characteristics that serve as both protective and risk factors in the context of CVD.


Some lower vertebrates such as zebrafish and axolotl have incredible cardiac regenerative potential while mammals have very limited ones. Comparative studies among species have revealed that cardiomyocyte polyploidy, endothermy, and injury-induced activation of certain transcriptional factors including AP1 complexes are critical for cardiomyocyte proliferation and heart regeneration during animal evolution. Gaining insights into these evolutionarily conserved mechanisms will likely lead to achieving heart regeneration in non-regenerative mammals including humans. Regenerative potential in the animal kingdom is a fundamental topic of regenerative biology and medicine. With the development of genome science and genetics technology, many investigators started to address how regenerative potential is lost or gained during the evolutionary courses of particular animal species. It is now documented that either whole-animal or organ regeneration is achieved by activating adult stem cells , by inducing Muller glia reprogramming into neurons in adult zebrafish retinas, or by promoting cardiomyocyte (CM) proliferation in adult zebrafish hearts, and neonatal mouse, rat, and pig hearts  are mononuclear diploid CMs during development, but they become mostly polyploid CMs at late gestation or early postnatal stages. The appearance of CM polyploidy conincides with the loss of cardiac regenerative potential in mice, rats, and pigs  increases CM proliferation and the percentage of MNCMs in neonatal and adult mice, and results in an evident improvement in cardiac function and fibrosis after myocardial ischemic reperfusion in adult mice. Consistently, exogenous application of thyroid hormone T3 inhibits heart regeneration with evident CM polyploidization and decreased CM proliferation in zebrafish. Thus, thyroid hormone signaling promotes CM polyploidy and decreases cardiac regenerative potential during animal evolution.Another elegant work has reported that the loss of cardiac regenerative potential is highly related with CM polyploidization via phylogenetic analysis of CM nucleation and polyploidy in a large collection of non-vertebrates and vertebrates, and the percentage of MDCMs inversely correlates with metabolic rate, body temperature, and serum total thyroid hormone T4 levels  for regulating CM nucleation and polyploidization, as well as non-coding DNA elements (regenerative enhancers) and binding factors (AP-1 complexes) for regulating CM proliferation. These and future studies will likely reveal a network of transcription factors and enhancers for coordinating CM proliferation and heart regeneration. In addition to these critical factors and regenerative enhancers, the field will take advantage of genome editing and chemical biology approaches to identify factors and small molecules that are sufficient for promoting non-regenerative heart regeneration in the coming years.


Of the estimated 16 million U.S. family members currently providing essential yet unpaid caregiving for persons with dementia (PWD), many will also make end-of-life (EOL) care decisions as surrogates, a process that can be fraught with uncertainty. Even with dementia death rates rising, many families delay advanced care planning (ACP) discussions, and surrogate decision makers often lack crucial information and support, implicating the need to further study this topic in aging. While decision aids (DA) serve as a support tool for caregivers, they can be less effective when failing to address unresolved decisional needs. Utilizing the Ottawa Decision Support Framework (ODSF), which asserts caregiver decision needs affect decision quality, this study sought to identify surrogate decision-support needs extending beyond general ACP. This mixed study used cognitive interviews and focus groups with family caregivers (N=13) and healthcare professionals (n=14) to assess their knowledge and understanding of hospice and artificial hydration and nutrition. Data were audio-recorded, transcribed verbatim, and analyzed with thematic content analysis. Three main themes were identified: DAs alone aren’t enough to foster quality decision making for surrogates; individualized communication is necessary to clarify PWD and caregiver value priorities and disease trajectories; and clarification of the impact of care choices within situational contexts is quintessential. Further development is needed to create a practice protocol from these themes to inform professionals assisting surrogates in ACP at EOL. Practical implications from this study include highlighting the importance of individualized communication between PWD, providers, and caregivers in addressing EOL care decisional needs.


Community-dwelling older adults often experience cognitive symptoms, and three common conditions that contribute to changes in cognition are dementia, depression and delirium. Despite the clinical inter-connectedness among these medical conditions, hereafter referred to collectively as cognitive vulnerability, little is known about the potential for success of clinical interventions that simultaneously address these conditions. From the perspective of older adults with cognitive vulnerability and their families, hospital admissions and emergency department (ED) visits are disorienting and often lead to declines in functional capacity and well-being, and significant family distress, threatening continued independent living. In this Symposium, we present details about an ongoing clinical trial testing a novel in-home, multidisciplinary team care management intervention for older adults with cognitive vulnerability and their families. This care management intervention led by nurse practitioners, called the3D Team care model, aims to help reduce ED visits and hospitalizations and achieve other health-related outcomes. The first presentation will provide study background and design features as well as characteristics of study participants. The next two presentations by the3D Team nurse practitioners will provide details about how the multidisciplinary team works, and how each team member provides interventions intended to address risk factors for adverse health outcomes. The fourth presentation by the3D Team community health educator will explain how needs related to social determinants of health are addressed. The Discussant will place this clinical trial within the broader context of multidisciplinary team care for older adults with cognitive vulnerability led by nurse practitioners trained in geropsychiatry.


Background：Gratifying the elderly health-care demands and promoting high-quality of nursing services are based on the effort of long-term care(LTC) nurses. However, the high turnover rate of LTC nurses has become very serious in China. What remains unclear is whether the organizational justice and job characteristics affect the LTC nurses’ intention to stay. Objective: The aim was to investigate intention to stay among LTC nurses in relation to organizational justice and job characteristics. Method: A cross-sectional study was conducted with a convenience sample of 545 LTC nurses. Data collection was performed between July and November 2019. Data were analyzed using structural equation modeling. Results: Most of LTC nurses reported to stay in nursing or current work place, however they still had strong desire to leave if there were other job opportunities. Organizational justice and job characteristics were significant predictors of LTC nurses intent to stay. LTC nurses job characteristics partially mediates the relationship between organizational justice and intent to stay. Conclusion: This would suggest the importance of administrators/ managers understanding how to promote organizational justice, foster a justice climate and increase LTC nurses’ perceived job characteristics. The organizational justice culture programs should be develop as LTC nurses retention strategy.


Post-traumatic bronchobiliary fistulas (BBF) are extremely rare with high morbidity and mortality rates. Accurate and timely diagnosis of these entities is critical for appropriate treatment, which usually requires a multidisciplinary approach. We describe two post-traumatic cases using a multimodality approach including computed tomography (CT), magnetic resonance imaging (MRI)/Magnetic Resonance Cholangiopancreatography (MRCP), and hepatobiliary scintigraphy with specific emphasis on the imaging features for each modality. Management of hepatobiliary fistulas is complex, involving extensive diagnostic work up followed by a conservative and/or surgical approach. Bronchobiliary fistula (BBF) is communication of biliary system and bronchial tree. It was first described by Peacock in 1850 . Post-trCase 1A 16-year-old male with history of penetrating injury (gunshot) to the right upper quadrant and right lower hemithorax complicated by biliary leak, diaphragmatic injury, and bilomas. Initial contrast-enhanced CT demonstrated multiloculated fluid collections in the right subphrenic space and small pleural effusion Figure , 1B . ThCase 2A 40-year-old male and victim of gun violence with surgical history of laparotomy, left hepatectomy, cholecystectomy and removal of two foreign bodies. Six days later, he underwent an endoscopic retrograde cholangiopancreatography (ERCP) which revealed extravasation of contrast from the common bile duct and he returned to the operating room for drainage of intraabdominal abscesses and a Roux-en-Y hepaticojejunostomy.Since then over several months he suffered from many hepatic abscesses, bilomas, cholangitis, and gram negative bacteremia, primarily managed with percutaneous drains and antibiotics. His clinical course was further complicated by misplaced drains and a biliarycutaneous fistula.Multiple admissions were made for management of the biliarycutaneous fistula, a most recent CT of the abdomen and pelvis demonstrated loculated collection in the hepatic dome extending into the right subdiaphragmatic space Figure , 2B. ThiThere is paucity of large case series in literature since post-traumatic BBFs are extremely uncommon. Most of the publications consists of case reports and small series. A systematic literature review of 68 cases published in 30 years by Liao et al. revealed only seven cases 10.2%) secondary to trauma [% secondaA significant clinical symptoms in patients with BBFs is bilioptysis. Bilioptysis is presence of bile in the sputum and believed to be pathognomonic finding for BBFs. Other common symptoms include irritating cough, fever, and jaundice .Penetrating injuries rather than blunt traumas are reported in etiology of bronchopulmonary fistulas . Both ofInitial evaluation usually starts with CT which is useful to demonstrate liver injury, abdominal and thoracic fluid collections, as well as abnormal lung findings. The widespread availability, decreased variability between operators, imaging speed, and relatively few contraindications make it ideal in immediate traumatic assessment ,8. HowevConventional MRI of the abdomen with MRCP (Magnetic Resonance Cholangiopancreatography) can provide good anatomical information of the biliary system. However, contrast-enhanced magnetic resonance cholangiography using hepatobiliary contrast agents was reported to demonstrate bronchobiliary fistula since it depicts biliary excretion from injured ducts . UnfortuHepatobiliary scintigraphy, similar to MR cholangiopancreatography with hepatobiliary contrast agents provide functional information. Image acquisition may be obtained for a prolonged time to trace bile movement. The precise location of bronchobiliary connection could not be confidently determined with this method even when SPECT was performed in the past. SPECT/CT as a hybrid imaging technique combining the functional information of hepatobiliary scintigraphy and anatomical information of CT overcomes the shortcoming and may clearly define fistulous tract .Management of BBF varies from a conservative approach to definitive surgical management. The conservative approach is preferred in the initial management of bile leaks. Biliary decompression or diversion using endoscopic sphincterotomy, biliary stent placement, or nasobiliary drainage and percutaneous image-guided catheter collections alone may be successful. More definitive treatment would require surgical resection of the fistula with pulmonary segmentectomy, especially in the presence of lung injury -15. ReceA multimodality approach is critical for stepwise diagnosis of BBFs. Although CT is used in initial evaluation of BBFs, hepatobiliary scintigraphy can confirm biliary leaks and differentiate bilomas from other fluid collections. Bile excretion and movement may be traced by sequential dynamic imaging. SPECT and more recently SPECT/CT may reveal connections between the bile ducts, bilomas and other structures such as bronchial tree and may play an important role in management of complex cases. MR cholangiopancreatography with hepatobiliary contrast agents also allows dynamic biliary imaging. It is an alternative to hepatobiliary scintigraphy and SPECT/CT and may demonstrate fistulous communications of the biliary system with high accuracy.


Motor impairments, including slow walking, are common in older age in the absence of prototypical Parkinson’s disease (PD). The etiology of such disturbances is heterogeneous and multi-system in nature. Dopamine is a key neurotransmitter involving motor, cognitive and behavioral circuitry. Normal aging is associated with substantial dopaminergic losses in the brain. Dopaminergic vulnerability of aging can be augmented by genotypic changes that may further compromise dopaminergic signaling, such as polymorphisms in the COMT gene. These observations may augur dopaminergic pharmacotherapy studies to treat gait disturbances in older adults. Prior dopaminergic therapy studies have shown overall limited effects in non-PD older adults. A major limitation of these studies is the non-targeted selection calling for personalized medicine approaches. Recent dopaminergic treatment studies targeting specific sub-groups of non-PD older adults conducted by us and others will be discussed.


In the coming years, inevitably growing numbers of older populations will yield more older Americans with extensive medical and long-term care needs. This will lead to an increasing need for long-term services and supports (LTSS) to assist older adults with routine daily activities . There is a growing interest in understanding how social and physical environments contribute to health outcomes and the provision of services and resources for older persons with disabilities requiring assistance from LTSS. Decisions about care and subsequent experiences are likely a result of factors that extend beyond personal preference or individual factors, such as neighborhood quality, housing context, and living situations  among community-dwelling older adults. Given population aging and the shift of LTSS from nursing homes toward community settings, there is a pressing need for more information about contextual factors that might help better develop supports for vulnerable older adults. This symposium will feature four presentations that provide novel insight regarding social and physical contextual factors contributing to LTSS. Presentations leverage data from the National Health and Aging Trends Study (NHATS), a nationally representative survey of Medicare beneficiaries aged 65 and older, and will describe: 1) associations between individual and home environment risk-factors, neighborhood-level social deprivation, and falls; 2) the relationship between neighborhood-level social deprivation and caregiving intensity (number of hours of caregiving per week) among community-dwelling older adults; 3) associations between living in single-family vs. multi-unit housing and social networks; and 4) community tenure among homebound older adults.


Novel technologies like navigation and robotic surgery are very costly and not easily available in all centres, especially in developing countries. We describe a simple method to assess the HKA alignment while performing coronal deformity correction around the knee using external fixator components which are commonly available with every centre.Coronal plane deformities of lower limb are often challenging and require a thorough pre-operative planning, accurate intra-operative assessment and execution. Intra-operative confirmation of correct restoration of lower limb alignment [Hip-Knee-Ankle (HKA) axis] is more often than not assessed by gross visual inspection, which can be fallacious. Various methods described in literature for intra-operative assessment include cable method, axis board, specialised alignment rods  with a connector, computer assisted surgeries, etcApparatus required for assessment of alignment includes external fixator rods and tube to tube connector clamps . ConnectWe have shown the application of this method using external fixator set from Greens® Surgicals Private Limited. However, external fixators from any manufacturer can be utilised for this purpose. We believe this simple method can be easily used by any orthopaedic surgeon in any centre without any additional efforts or cost.


Neural injury in mammals often leads to persistent functional deficits as spontaneous repair in the peripheral nervous system (PNS) is often incomplete, while endogenous repair mechanisms in the central nervous system (CNS) are negligible. Peripheral axotomy elicits growth-associated gene programs in sensory and motor neurons that can support reinnervation of peripheral targets given sufficient levels of debris clearance and proximity to nerve targets. In contrast, while damaged CNS circuitry can undergo a limited amount of sprouting and reorganization, this innate plasticity does not re-establish the original connectivity. The utility of novel CNS circuitry will depend on effective connectivity and appropriate training to strengthen these circuits. One method of enhancing novel circuit connectivity is through the use of electrical stimulation, which supports axon growth in both central and peripheral neurons. This review will focus on the effects of CNS and PNS electrical stimulation in activating axon growth-associated gene programs and supporting the recovery of motor and sensory circuits. Electrical stimulation-mediated neuroplasticity represents a therapeutically viable approach to support neural repair and recovery. Development of appropriate clinical strategies employing electrical stimulation will depend upon determining the underlying mechanisms of activity-dependent axon regeneration and the heterogeneity of neuronal subtype responses to stimulation. Following injury to the adult mammalian central nervous system (CNS), neural circuits are permanently disrupted as severed axons fail to undergo spontaneous regeneration. The limited regenerative response of injured CNS neurons is due to both intrinsic and extrinsic factors. These growth-restrictive mechanisms play a large part in the poor clinical outcomes following brain or spinal cord trauma; however, despite limited regenerative capacity, mounting evidence has shown extensive spontaneous sprouting of CNS axon collaterals in the injured adult CNS.The mammalian nervous system has an intrinsic capacity for structural and functional reorganization in response to a variety of stimuli during development, learning, or in response to pathological insults . This inRecent findings suggest that manipulation of neuronal activity can drive plasticity related growth mechanisms and augment collateral sprouting, thereby enhancing the functional effect of axonal remodeling . ElectriIn contrast to most CNS neurons, neurons of the peripheral nervous system (PNS) have a more robust regenerative response to injury . This owDespite the innate regenerative potential of PNS neurons after injury, recovery of function remains limited. Several factors can hamper recovery, such as age, extent of injury and disruption of endoneurium, perineurium, or epineurium, and neuroma formation. One critical factor is the slow rate of regeneration in the adult PNS of 1–3 mm per day . Axons nThe innate regenerative ability of adult mammalian PNS neurons has been used as a model to study the intrinsic mechanisms underlying the regenerative program. Primary sensory neurons are located in the DRG and extend axons into both CNS and PNS. Each axon exhibits a distinct response to injury in the adult. As described above, the peripheral axon retains the ability to regenerate following axotomy. In contrast, the CNS axon of the same cell will fail to regenerate after spinal cord injury. Intriguingly, the regenerative program activated by peripheral nerve injury conditions DRG neurons to mount an enhanced regenerative response to a second injury, whether in the peripheral or central axon . The proAnother important change after conditioning lesion is the transient increase of second messenger cyclic nucleotide cAMP levels. Artificial elevation of cAMP can support a limited amount of sensory axon regeneration in the injured spinal cord . DownstrActivation of the pro-regenerative transcriptional response in the somata of regenerating neurons requires a retrograde signal from the injury site. One candidate for this rapid signal is the early influx of calcium at the injury site . Rapid cin vitro injury  stimulation   . Nitric (CamKII) . Piezo-m in vivo . Further in vivo . Genetic calcium . Blockad in vivo .PTEN deletion from RGCs and other CNS neurons leads to elevated PI3K/mTOR  signaling, enhanced phosphorylation of S6, and an increased capacity for axonal growth after injury  by high-contrast visual stimulation or via chemogenetics approaches can enhance optic nerve regeneration . In contr injury . Alternadeletion .suppressor of cytokine signaling 3 (SOCS3) increases optic nerve regeneration  have been largely defined as the coordinated and complementary genes activated by peripheral conditioning paradigms in PNS neurons. These include developmental growth-associated proteins , transcription factors , and signaling pathways  . In muchWhile electrical stimulation activates many of the same molecular pathways as peripheral conditioning via crush injury, it does not fully recapitulate the growth-promoting effects of conditioning. Following a subsequent peripheral injury, previous exposure to low-frequency electrical stimulation enhances the initiation of regeneration, but does not increase the rate of peripheral motor or sensory axon regeneration . The limin vivo by low frequency (20 Hz) electrical stimulation, 20 Hz trains separated by 5 min intervals arrested neurite outgrowth of primary sensory neurons in vitro  stimulation of the soleus muscle in the rabbit was used to shorten the time for recovery of soleus function after axonotmesis of the soleus motor nerve . This mod injury  is likeld injury .trans-spinal direct current stimulation after cervical spinal cord injury results in a strengthening of novel connections in the spinal cord. Furthermore, this paired stimulation paradigm can support the recovery of dextereous forelimb movements that depend on corticospinal function  is a non-invasive and painless neuromodulation strategy that augments motor and sensory function after SCI . CervicaAmong the different approaches that have been proposed to enhance post-lesion plasticity, extrinsic manipulation of neuronal activity by electrical stimulation is an attractive therapeutic approach. Electrical stimulation has been demonstrated to engage plasticity mechanisms in several central and peripheral neural circuits and has already shown feasibility in clinical settings. Development of appropriate strategies will likely depend upon the selective activation of desired neural subtypes in a temporally and spatially organized manner. Non-targeted electrical fields have been used to trigger population responses; however, it may be that distinct electrical stimulation parameters can selectively affect neuronal subtype responses and circuit-specific functional outcomes. Whether the molecular mechanisms activated by electrical stimulation are consistent across neuronal populations is unknown. The sprouting response of corticospinal axons to electrical stimulation contrasts with the elongation observed in stimulated PNS axons. These differences may arise from disparate stimulation parameters, discrete responses of these distinct populations to electrical stimulation, or from interactions of conserved stimulation-mediated molecular pathways with the intrinsic limitations of adult CNS neurons to axon elongation. Further studies will be required to identify whether CNS-tuned parameters of electrical stimulation can drive a regenerative response in transected corticospinal axons.In the context of SCI, preclinical and clinical studies have clearly demonstrated that the stimulation of local spinal networks can drive lasting functional improvements . CorticaJJ and EH wrote and edited the manuscript. SA created the illustrations. All authors contributed to the article and approved the submitted version.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.


We summarize how older women face intersectional experiences that affect their retirement security. These include differential trends in aging, life expectancy, labor supply, work history, retirement savings, and poverty at old age. We also highlight research showing that older women experience significantly more age discrimination than older men. affecting the ability for older women to improve their retirement security by working longer. We demonstrate through examples that these differential trends and intersectional experiences of older women have important policy implications. We provide examples of how Social Security policies, such as increases in the full benefit retirement age and changes to the retirement earnings test, have differential effects on older women. We also discuss how age and gender employment discrimination law fails to protect older women from intersectional sex-plus-age discrimination. We conclude by urging policymakers to consider how older women experience different challenges and how policy should consider their unique experiences.


High-grade gliomas are the most common and aggressive malignant primary brain tumors. Current therapeutic schemes include a combination of surgical resection, radiotherapy and chemotherapy; even if major advances have been achieved in Progression Free Survival and Overall Survival for patients harboring high-grade gliomas, prognosis still remains poor; hence, new therapeutic options for malignant gliomas are currently researched. Sonodynamic Therapy (SDT) has proven to be a promising treatment combining the effects of low-intensity ultrasound waves with various sound-sensitive compounds, whose activation leads to increased immunogenicity of tumor cells, increased apoptotic rates and decreased angiogenetic potential. In addition, this therapeutic technique only exerts its cytotoxic effects on tumor cells, while both ultrasound waves and sensitizing compound are non-toxic per se. This review summarizes the present knowledge regarding mechanisms of action of SDT and currently available sonosensitizers and focuses on the preclinical and clinical studies that have investigated its efficacy on malignant gliomas. To date, preclinical studies implying various sonosensitizers and different treatment protocols all seem to confirm the anti-tumoral properties of SDT, while first clinical trials will soon start recruiting patients. Accordingly, it is crucial to conduct further investigations regarding the clinical applications of SDT as a therapeutic option in the management of intracranial gliomas. Intracranial gliomas are the most common primitive malignant neoplasms of the central nervous system, accounting for approximately 24.1% of all primary brain tumors .,56.55,56


This pilot study assessed a novel intervention to enhance both walking and executive function in older adults. The primary hypothesis was that eighteen sessions of frontal lobe tDCS combined with walking rehabilitation would be feasible, safe, and show preliminary efficacy. Eighteen participants were randomized to one of three intervention groups: active tDCS and rehabilitation with complex walking tasks (Active/Complex); sham tDCS and rehabilitation with complex walking tasks (Sham/Complex); or sham tDCS and rehabilitation with typical walking . Outcome measures included multiple tests of walking function, executive function, and prefrontal activity during walking as measured by functional near infrared spectroscopy (fNIRS). Of the three groups, the Active/Complex group demonstrated the broadest improvements across outcome measures including for prefrontal activity. The functional range of prefrontal activity in this group was increased considerably, as conceptualized by the Compensation Related Utilization of Neural Circuits Hypothesis. Frontal tDCS is a promising adjuvant to walking rehabilitation.


Older adults’ psychosocial factors, including personality, are correlated with driving performance and driving cessation. However, the relationship between personality and driving styles has been examined only among young and middle-aged drivers. This study examined the relationships of personality factors and self-reported driving styles among 72 healthy older drivers aged 65-85  using the Multidimensional Driving Style Inventory (MDSI) scale to measure reckless and careless, anxious, angry and hostile, and patient and careful driving styles. Personality was accessed with the Big Five Personality questionnaire. Correlational results indicated that less conscientiousness was significantly correlated with increased reckless and careless and less patient and careful driving styles; and lower agreeableness was significantly correlated with greater angry and hostile and less patient and careful driving styles. Being a man was associated with greater reckless and careless and angry and hostile driving styles. Age was not associated with driving styles. Accordingly, three regressions were tested. After controlling for gender, only lower conscientiousness was associated with greater reckless and careless driving style . Men had a higher risk of reckless and careless  and angry and hostile  driving styles. Our results highlight the relationship between personality traits and self-reported driving styles among older adults, and how gender may influence some of these relationships. Future research should further investigate the associations between gender and personality traits and older adults’ driving mobility and safety.


Certain emotion regulation (ER) strategies are often considered to be more or less demanding of cognitive resources. However, age-related differences in the perceptions of these demands are not yet understood. Older adults might perceive greater demands for certain strategies due to differences in cognitive ability and motivation to maintain emotional well-being. In the present study, we examined age and cognitive ability as predictors of perceived effort required to use ER strategies that span all families of the process model. A diverse sample of community participants (age 22-83) completed assessments of cognitive ability and perceived demands associated with ten ER strategies. Overall, response-focused strategies were rated as highest in demands whereas situation selection and savoring were perceived as least demanding. Older adults reported higher demands associated with situation selection, distraction, and detached reappraisal  compared with younger adults. Cognitive ability was not associated with perceived demands for ER strategies traditionally viewed as cognitively demanding . Rather, higher cognitive ability only predicted lower perceived demands for strategies often considered low in demand: situation selection and savoring. Perceived ER success was not consistently associated with age or cognitive demands. Results suggest that older adults view some, but not all, ER strategies as more demanding than younger adults do. The role of cognitive ability in age-related changes in ER may be more complex than previously expected. Notably, the lack of findings with perceived ER success suggest effort requirements associated with ER may not impede ability to successfully regulate across adulthood.


E. coli and quantify ppGpp within several strains using a recently developed analytical method. We find that although the inverse correlation between ppGpp and growth rate is robust across strains and analytical methods, absolute ppGpp concentrations do not absolutely determine RNA synthesis rates. In addition, we investigated the consequences of two separate RNA polymerase mutations that each individually reduce (but do not abolish) sensitivity to ppGpp and find that the relationship between ppGpp, growth rate, and RNA content of single-site mutants remains unaffected. Both literature and our new data suggest that environmental conditions may be communicated to RNA polymerase via an additional regulator. We conclude that basal ppGpp is one of potentially several agents controlling ribosome abundance and DNA replication initiation, but that evidence for additional roles in controlling macromolecular synthesis requires further study.The molecule guanosine tetraphophosphate (ppGpp) is most commonly considered an alarmone produced during acute stress. However, ppGpp is also present at low concentrations during steady-state growth. Whether ppGpp controls the same cellular targets at both low and high concentrations remains an open question and is vital for understanding growth rate regulation. It is widely assumed that basal ppGpp concentrations vary inversely with growth rate, and that the main function of basal ppGpp is to regulate transcription of ribosomal RNA in response to environmental conditions. Unfortunately, studies to confirm this relationship and to define regulatory targets of basal ppGpp are limited by difficulties in quantifying basal ppGpp. In this Perspective we compare reported concentrations of basal ppGpp in  Escherichia coli, the small molecule guanosine tetraphosphate (ppGpp) is closely tied to growth rate control. However, due to the circumstances of its discovery, ppGpp is more familiar as a stress or starvation signal. ppGpp and guanosine pentaphosphate (pppGpp), collectively called (p)ppGpp, were first identified in E. coli as compounds produced in strains that inhibit stable RNA synthesis upon amino acid starvation, a phenomenon known as the stringent response (–1 for ppGpp) (E. coli (How might a bacteria cell measure its own growth rate? In the model bacterium response . The souresponse . The higr ppGpp)  drive prr ppGpp) . The ove(E. coli  we focusE. coli in the absence of stress (between 10 and 90 pmol OD–1). When growth rate is varied by nutritional quality, basal ppGpp correlates inversely with growth rate. Basal ppGpp is essential in minimal media as it is required to activate transcription of amino acid pathways ppGpp0] does not vary DNA replication initiation in response to growth rate, suggesting that ppGpp participates in regulating the DNA-biomass ratio  like an emergency brake.The observation that high ppGpp concentrations inhibit biomass synthesis suggests that basal ppGpp concentrations might also directly regulate all biomass synthesis pathways during steady-state growth, in addition to regulating stable RNA synthesis. This hypothetical layer of regulation would complement control of rRNA transcription, which determines the maximum rate of is PurF,  or transis PurF,  or the fis PurF, . Basal pis PurF, , as highis PurF, . In thisE. coli controls growth. To further encourage the recent revival of interest in the mechanisms of steady-state growth regulation and homeostasis  its low abundance; (2) its chemical instability; (3) the presence of environmentally sensitive enzymes that rapidly hydrolyze and synthesize ppGpp. This means the analytical method must both chemically stabilize ppGpp and immediately denature all enzymes that synthesize or hydrolyze ppGpp. Moreover, in order to study ppGpp dynamics relevant to the rapid ppGpp response (<5 s), the method must enable fast sampling.Actual ppGpp measurements are essential for determining which cellular processes are watching the growth rate speedometer. The rarity of basal ppGpp measurements is understandable as basal ppGpp is difficult to accurately quantify. The main challenges in measuring basal ppGpp Despite these difficulties, several (p)ppGpp measurement methods have been developed, including thin layer chromatography (TLC) , high peA survey of reported basal ppGpp concentrations combined with our own measurements  indicateE. coli show an inverse correlation between growth rate and basal ppGpp (15–90 pmol OD–1)  . Early sol OD–1) . Khan aned trend . Howevered trend .Reported ppGpp concentrations may differ perhaps due to differences in strains, turbidimeter calibration, or sampling method . InteresE. coli K-12 strains using LC-MS (rph+ but not isogenic with the MG1655 reported here) has been used to demonstrate correlation between the RNA/protein ratio and the growth rate  artificially elevates ppGpp, inhibits rRNA synthesis and decreases growth rate. Data from ppGpp titrations using RelA′ are compared in E. coli NCM3722 in both LB medium and glucose minimal medium yields a ppGpp-growth rate curve steeper than the curve obtained in nutrient-limited NCM3722   . Howeverincreases in parallel with growth rate. E. coli mutants unable to synthesize specific nucleotides [carAB- guaB(ts)]. When growth rate was titrated with pyrimidine and purine sources, the authors inverted the correlation between ppGpp and growth rate  supply? First, uracil limitation does not activate ppGpp synthesis in wild-type strains , indicatE. coli glucose cultures. Pseudomonic acid causes accumulation of uncharged tRNA and increases ppGpp. High concentrations of pseudomonic acid abruptly increased ppGpp and rapidly arrested growth, consistent with the stringent response. Low concentrations of pseudomonic acid also triggered ppGpp synthesis (up to 60–100 pmol OD–1) and an immediate but smaller decrease in rRNA synthesis. However, the instantaneous growth rate  was not perturbed in the short term by small increases in ppGpp concentrations.Steady-state correlations such as the correlation between ppGpp and growth rate imply but do not establish regulatory connections. Hypotheses inspired by correlations must be tested by environmental perturbations. –1) do not seem to immediately inhibit biomass synthesis (with the exception of stable RNA). This undermines any notion that basal ppGpp directly regulates the instantaneous translation rate. Finally, two additional studies demonstrate that ppGpp and the rate of stable RNA synthesis can be transiently decoupled during nutritional upshifts, suggesting that additional signals may regulate rRNA synthesis  retains regulation by basal ppGpp if its two ppGpp binding sites are disrupted, we measured basal ppGpp levels, growth rates and cellular RNA in  mutants , 2016. ArpoZ(wt) rpoC R362A R417A K615A; rpoC N680A K681A; We transferred mutations that disrupt ppGpp binding site 1 [rpoC2- mutant in LB medium. At first glance, this is consistent with the notion that the RNAP mutants are less sensitive to ppGpp, as apparent from the slopes of cellular RNA content vs. ppGpp (P < 10–6). In other words, higher ppGpp concentrations may be required to inhibit RNA synthesis in these strains. While it might be expected that the cultures expressing ppGpp-insensitive RNAP thus contain a higher RNA abundance than wild-type, we found that for every medium aside from MOPS/acetate, both mutant strains exhibit equivalent or even less RNA per OD unit than does the wild-type  deserve fuller exploration as they likely hint at poorly understood facets of ppGpp biology. Disrupting either individual ppGpp binding site of RNAP did not eliminate the correlation between growth rate, RNA content, and basal ppGpp concentrations. Despite compelling evidence for basal ppGpp control of rRNA synthesis, incorporating ppGpp into quantitative models of cell behavior requires a better understanding of both transcriptional and post-translational targets. In order to advance this goal, we suggest several questions for the field:1.What targets are responsive to basal ppGpp concentrations? As basal ppGpp varies with growth rate in parallel with all biosynthetic fluxes during balanced growth, it is tempting to overextend models of ppGpp control. Targets thought to be regulated during the stringent response may prove insensitive to basal ppGpp. Experiments that monitor ppGpp during growth transitions already suggest that small changes in basal ppGpp do not immediately affect instantaneous protein synthesis or total biomass production. Studies of basal ppGpp concentrations during growth transitions are essential for distinguishing what is influenced by ppGpp. We suggest experiments that monitor protein synthesis during small controlled variations in basal ppGpp (±50 pmol OD–1).2.What establishes basal ppGpp concentrations? It is unknown which metabolic cues drive RelA and SpoT to generate basal ppGpp.3.What regulates stable RNA synthesis during steady-state growth, aside from basal ppGpp? Our observation that RNA polymerase mutants lacking either one of the two ppGpp binding sites still exhibit an inverse relationship between RNA content and ppGpp concentrations implies that other factors also regulate RNA content, as has been suggested  would also determine whether basal ppGpp is an accurate growth rate speedometer.5.Do all species with RSH proteins also maintain basal concentrations of ppGpp (or pppGpp) during steady-state growth? As RSH proteins are widely distributed  and defined media to enable comparisons between labs.We further recommend the use of common reference strains (preferably All datasets generated for this study are included in the article/NI and GB conceived and designed the experiments and wrote the manuscript. NI performed experiments and data analysis. NI, NB, and MN developed the LC-MS method. All authors contributed to the article and approved the submitted version.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.


This study compared gait speed changes after CSF tap test in patients with idiopathic normal pressure hydrocephalus presenting with various gait phenotypes . All patients improved, except those with parkinsonian gait. Gait disorders are the hallmark feature of patients with idiopathic normal pressure hydrocephalus (iNPH) /[(gait speedpost-CSF tap test + gait speedpre-CSF tap test)/2]. Univariable linear regressions evaluated the relationship between gait speed changes  and each gait phenotype . Multivariable linear regressions were adjusted for age, gender, comorbidities, white matter changes assessed by the age-related white matter change scale . Frontal gait was significantly associated with gait speed improvement after CSF tap test, even after adjusting on age, gender, comorbidities, white matter changes, and MMSE . Normal gait, parkinsonian gait, and other gait abnormalities were not significantly associated with gait speed improvement, after adjusting on age, gender, comorbidities, white matter changes, and MMSE .Clinical characteristics are presented in Table This study showed that gait improvement after CSF tap test varies across gait phenotypes: frontal gait is associated with the greatest gait improvement after CSF tap test, while patients with parkinsonian gait did not show any significant gait speed changes.p value < 0.001). Patients with frontal gait presented the lowest gait speed at baseline and, therefore, had the greatest potential of improvement, as previously described  may be explained by the following reasons. First, patients were included at an early stage of the disease course, where clinical gait abnormalities may not be evident. Second, patients have been referred, because the suspicion of iNPH was solely based on cognitive impairment and/or urinary incontinence. Third, patients may complain of gait impairments in challenging situations  or balance impairments that were not clinically evident in the secure setting of a gait laboratory. Fourth, they presented fewer comorbidities that may affect gait. These results suggest that CSF tap test could also be considered at the earliest stages of iNPH when patients complain about their gait, but no clinical gait abnormality is diagnosed by physicians.The variability of the gait phenotypes in our cohort of iNPH patients may be explained by comorbidities . However, the validity of the clinical examination  is not perfect and prone to an interrater variability. Having a better quantification of neurological and non-neurological comorbidities would allow a better sense of the influence of comorbidity on each gait phenotype. A post-mortem pathological examination is missing and would be of interest, especially in this cohort including mainly patients with possible iNPH (87%), who may present either a comorbid neurological condition along with iNPH or present an iNPH mimic. Finally, future studies should confirm these results by evaluating the predictive value of clinical gait phenotypes after shunting.Among gait phenotypes, frontal gait in patients with iNPH is associated with the largest gait improvement after CSF tap test. This study suggests that a clinical classification of gait phenotypes in patients with iNPH may inform about the reversibility of gait disabilities. Future studies should include long-term clinical outcomes after shunt procedure to confirm that frontal gait in iNPH patients may present a good clinical outcome in comparison to other gait phenotypes.


Calcifications play an essential role in early breast cancer detection and diagnosis. However, information regarding the chemical composition of calcifications identified on mammography and histology is limited. Detailed spectroscopy reveals an association between the chemical composition of calcifications and breast cancer, warranting the development of novel analytical tools to better define calcification types. Previous investigations average calcification composition across broad tissue sections with no spatially resolved information or provide qualitative visualization, which prevents a robust linking of specific spatially resolved changes in calcification chemistry with the pathologic process.Method: To visualize breast calcification chemical composition at high spatial resolution, we apply hyperspectral stimulated Raman scattering (SRS) microscopy to study breast calcifications associated with a spectrum of breast changes ranging from benign to neoplastic processes, including atypical ductal hyperplasia, ductal carcinoma in situ, and invasive ductal carcinoma. The carbonate content of individual breast calcifications is quantified using a simple ratiometric analysis.Results: Our findings reveal that intra-sample calcification carbonate content is closely associated with local pathological processes. Single calcification analysis supports previous studies demonstrating decreasing average carbonate level with increasing malignant potential. Sensitivity and specificity reach >85% when carbonate content level is used as the single differentiator in separating benign from neoplastic processes. However, the average carbonate content is limiting when trying to separate specific diagnostic categories, such as fibroadenoma and invasive ductal carcinoma. Second harmonic generation (SHG) data can provide critical information to bridge this gap.Conclusion: SRS, combined with SHG, can be a valuable tool in better understanding calcifications in carcinogenesis, diagnosis, and possible prognosis. This study not only reveals previously unknown large variations of breast microcalcifications in association with local malignancy but also corroborates the clinical value of linking microcalcification chemistry to breast malignancy. More importantly, it represents an important step in the development of a label-free imaging strategy for breast cancer diagnosis with tremendous potential to address major challenges in diagnostic discordance in pathology. Calcifications associated with breast disease are critical to breast cancer screening as they are often the only discernible indicator of risk in mammography Despite their diagnostic and prognostic potential, the morphologic and chemical features of calcifications are poorly understood, in part due to technological limitations. Morphological features of calcifications identified by mammography are insufficient for accurate diagnosis and prognosis. In addition, smaller calcifications (<0.1mm) are undetectable using mammography Moving beyond morphology and distribution patterns in breast calcification, studies utilizing X-ray diffraction and electron microprobe analysis with scanning electron microscopy (SEM) have contributed to an earlier understanding of calcification chemical differences While offering information about calcification chemistry, most spectroscopic methods average calcifications within multiple ducts within a tissue section, irrespective of the heterogeneous pathologic processes among adjacent ducts. Spatially resolved methods such as FTIR imaging have limited resolution and throughput, prohibiting visualization of calcification composition variation within adjacent ducts and lobules. Moreover, tissue protein content is recognized to correlate with malignancy We utilize the high resolution and chemical specificity SRS offers to deliver an unprecedented level of detail when analyzing calcifications. Additionally, we incorporate second harmonic generation (SHG) which has been proven effective at visualizing collagen in the tumor microenvironment -1 for total of 90 frames per stack. For SHG, a dichroic mirror (Chroma 695dcxr) is placed before the objective to allow for epi-collection of SHG signal from the sample. The SHG signal is detected by a photo-multiplier tube (Hamamatsu H10770PA-40) using 485 nm long pass and 650 nm short pass filters.A broadband femtosecond dual-beam laser system (Insight DS + from Spectra-Physics) was used for SRS and SHG Figure . The detCalcium hydroxyapatite (HAP) and 10% carbonated hydroxyapatite (CHAP) were obtained from Sigma Aldrich and Clarkson Chromatography Products respectively. Both solid controls were ground using mortar and pestle. A total of five mixtures were prepared for calibration purposes . The calibration samples were placed between a coverslip and a microscope slide for SRS imaging.Breast tissue was obtained from 17 patient archival cases (including biopsy and resection) managed by Northwest Biotrust, Seattle, WA. The initial case selection was based on the pathology report . Slides were subsequently reviewed to confirm the histologic diagnoses . Formalin-fixed paraffin-embedded tissue blocks were retrieved from archives and sectioned at 4-microns and mounted on charged slides. One section was H&E stained to identify pathological process. The adjacent section was deparaffinized and coverslipped for SRS and SHG analysis. The areas of interest were identified in the bright field based on selected areas of interest on adjacent H&E stained slides. A total of 214 breast calcifications were imaged, including: 31 non-neoplastic calcifications , 27 fibroadenoma (FA) associated calcifications, 8 atypical ductal hyperplasia (ADH) associated calcifications, 36 ductal carcinoma in situ (DCIS) associated calcifications, 112 invasive ductal carcinoma (IDC) associated calcifications. -1) and phosphate (~960 cm-1) peaks corrected for background Calibration samples with 0%, 2.5%, 5.0%, 7.5%, 10% carbonate content in calcium hydroxyapatite mixtures were imaged using the hyperspectral SRS microscope described above. Using SRS intensities at carbonate (~1070 cm-1) was used to visualize tissue morphology of the FOV  the average, for a given category , was calculated with the standard deviation reported as an error bar. The differences between categories were assessed using p-values calculated from Student's t-tests. The receiver operator curves (ROC) were calculated using R software to assess the sensitivity and specificity for each parameter. Maximum Youden's index was used to determine sensitivity and specificity values.Previously, the carbonate content in hydroxyapatite has been measured using RS Figures Breast tissue submitted for pathological examination often contains calcifications in multiple ducts, which may represent various pathologic processes. In previous spectroscopic studies, multiple ducts are frequently measured together, which can average calcifications associated with different processes. Isolating individual breast ducts and detailing the histopathology within the ducts allows for correlation of variation in carbonate content with local pathology.Here, we group calcifications by specific pathological processes and not by overall case diagnosis. In Figure Figure The two cases illustrate that calcifications in the same patient case can have differing chemical composition. Although ducts are present in the same tissue section, the carbonate content associated with individual ducts is markedly different and reflects underlying pathological process. The high spatial resolution of hyperspectral SRS imaging is important to resolve calcification heterogeneity within the same patient sample and to establish the relationship between chemical composition and pathological process.Previous studies using FTIR have demonstrated that breast calcifications with lower carbonate content of CHAP correlate with malignancy Figures The neoplastic progression from benign ducts to IDC is associated with an overall decrease in calcification carbonate content Figure F and 6G Although precise quantification of the spatial distribution of carbonate in large calcifications is challenging due to sectioning artifact, our findings suggest that the carbonate content decrease on the edges of the calcifications directly reflects the changing microenvironment (i.e. higher acidity) associated with neoplastic cells and necrotic debris -1) to phosphate (~960 cm-1) ratio is used to quantify protein content in calcifications  and specificity (88%) when identifying benign and invasive processes. SHG data provides a parameter separating FA from IDC cases with high sensitivity (94%) and specificity (85%). Phenylalanine to phosphate ratio provides additional separation between DCIS and IDC. Together, spectroscopy and morphology can be utilized to better establish the malignant potential in cases with ambiguous morphology on H&E alone.CHAP is not the only microcalcification species that was identified in breast cancer. Although whitlockite typically accounts for a tiny percentage of breast calcifications -1 to 970 cm-1) Typically, whitlockite can be identified using Raman spectroscopy due to unique spectral features . This problem can be addressed in future studies by imaging either fixed tissue or fresh tissue, where calcifications remain intact.Besides carbonate content of calcifications, we have elucidated the unique features that distinguish chemical composition of calcifications between FA and IDC. For the first time, we demonstrate that SHG data confirms collagen in FA makes an organic matrix upon which hydroxyapatite accumulates. This matrix observed in FA calcifications is one of the main differences between FA and IDC. This collagen matrix enables robust differentiation of FA and IDC, which exhibit similar carbonate content.In conclusion, we imaged a diverse set of breast calcifications associated with benign processes, and a range of neoplastic processes including FA, ADH, DCIS and IDC. Our findings support previous reports of carbonate content decreasing on average with increasing malignant potential. Importantly, we showed that a detailed spatial map of calcifications and their complex underlying organic matrix is highly correlated with underlying neoplastic processes and could potentially be used for breast cancer diagnosis. Additionally, the spatial heterogeneity of carbonate content could potentially be a diagnostic indicator of malignancy. Calcification underlying organic matrix, visualized using SHG in conjunction with SRS, assisted in the diagnostic differentiation of patient lesions. Our study suggests that SRS imaging of calcification can be used as an important tool for breast cancer diagnosis. The diagnosis capability will be significantly improved when combined with stimulated Raman histology (SRH), a technique that has already been shown to provide H&E equivalent information in unsectioned tissue Supplementary figures and tables.Click here for additional data file.


Recent changes in health care practices - shorter hospital stays, increased complexity of disease management, and greater management of chronic illnesses at home - have left family members increasingly responsible for medical tasks. Although these family caregivers represent the vital front line of care, they remain mostly excluded from the formal health care team. Based on interviews with multi-sector stakeholders representing patients/caregivers, providers, and payers, we identified several barriers to fully incorporating family caregivers into the health care team. They fall under five key themes: identification of caregivers; communication and information; time and resources; trust and cultural barriers; and Medicaid coverage. We discuss these barriers and potential solutions that could be undertaken by different stakeholder groups to improve family caregiver integration into the care team.


The number of older populations raising their grandchildren has increased. Past research has indicated the distress custodial grandparents’ experience is related to their family relationships . Family relationships are also influenced by a variety of factors such as social history, culture, family structure, and individual differences . The current study evaluated the influence of culture on the relationship between caregiver relationship quality and mental health by examining 885 children . This study also compared the difference in cultural impact between custodial grandparents-grandchildren and biological parents-children. Measures included the Network of Relationships Inventory, Hofstede Cultural Questionnaire, and Adult Behavior Checklist. Path analysis was conducted using AMOS 26.0 which resulted in an interaction between relationship closeness and collectivism to predict custodial grandparent depressive symptoms. Custodial grandparents who reported a lower level of closeness with their grandchildren in a higher collectivistic culture reported a significantly higher level of depression symptoms than those in a more individualistic culture, particularly for custodial grandmothers. However, custodial grandparents who reported a higher level of closeness with their grandchildren in a higher collectivistic culture reported significantly lower levels of depressive symptoms than those in a more individualistic culture. Furthermore, compared to biological parents, custodial grandparents reported significantly lower levels of depressive symptoms when reporting higher collectivistic culture. These findings will inform the need for more research to assess factors of cultural features that reduce psychological problems and support family relationships to adapt psychological therapies in older adults.


This study examined the relationships between several attributes of living environment and attitudes towards aging among persons of age 75 years and older in Shanghai, China. The data were collected using self-administered surveys in a study of successful aging in 2018. Respondents included 139 persons of age 75 years and older living in 12 neighborhoods in Shanghai. Attitudes towards aging were measured by indices of happiness, time use and worry about the future. Using BaiduMap and GIS ArcPro, we quantified accessibility to neighborhood living resources as numbers of recreational facilities, medical facilities, parks, and grocery stores located within 500 meters of each respondent’s home. The analysis found that more positive attitudes towards aging were correlated with less depressive symptom as measured by CES-D and greater numbers of neighborhood resources near home, especially greater number of grocery stores near home. In conclusion, accessibility to neighborhood resources may influence attitudes towards aging.


As a consequence of the Affordable Care Act’s enhancements of Medicare benefits, certain recommended clinical preventive services became available to Medicare beneficiaries without cost-sharing. We study the impact of these mandates on racial/ethnic disparities in the use of preventive services among traditional Medicare beneficiaries. We analyze nationally representative data on non-institutionalized Medicare seniors from the 2006-2016 Medical Expenditure Panel Survey . Our preventive services of interest include yearly receipt of cholesterol check, blood pressure test, flu shot, endoscopy, blood stool test, clinical breast examination, mammography and prostate exam. We estimate propensity score weighted difference-in-difference (DID) models to test for differences in preventive services utilization by race/ethnicity. Among traditional Medicare beneficiaries, we do not observe significant change in the use of most preventive services for Blacks and Hispanics compared to their White counterparts. However, Hispanics have significantly increased their use of blood stool tests relative to whites. Overall, we do not find major evidence to support a differential effect of reforms on race/ethnic minorities’ uptake of preventive services following the mandates. Our results suggest that despite an overall benefit trough services expansion and cost-sharing elimination race/ethnic group differences persist. As such, disparities might continue and would require additional interventions. Reduction in disparities is a stated goal of US policy for many decades and achieving equity might require additional work and more varied and targeted interventions.


Metastatic cancer patients undergo numerous treatment strategies with known cognitive side effects. It is unclear how medical decision-making capacity (MDC) is impacted by cognitive deficits in metastatic cancer. This study examines reliability of an objective measure of MDC compared with self-report. Participants with newly diagnosed metastasis to the brain and other sites were enrolled at the University of Alabama at Birmingham over seven years. At the study visit, participants completed a comprehensive neuropsychological battery including memory and executive functioning, and the Capacity to Consent to Treatment Instrument (CCTI) assessing medico-legal domains of MDC. The CCTI is a reliable and valid instrument containing two vignettes of hypothetical medical situations assessing four standards of consent. We examined reliability between the CCTI and self-reported MDC using Gwet’s AC1 statistic. Participants with brain metastasis with impairment on the CCTI demonstrated significantly lower executive functioning and memory skills than those without impairment . There were no significant differences between intact and impaired participants with other metastases. Low reliability was observed between self-report and all medico-legal standards on the CCTI across both metastatic groups . Self-rating of MDC is unreliable in metastatic cancer patients. Patients with metastases (particularly brain metastases) may lack awareness of deficits in their MDC, so providers must affirm proper autonomy in their decisions.


A paradoxical double challenge has emerged in the last decades with respect to nutrition and nutrition-related clinical conditions. Hunger-related undernutrition continues to represent an unacceptable burden, although its prevalence has been encouragingly reduced worldwide. On the other hand, the prevalence of overweight and obesity, defined as fat excess accumulation with negative impact on individual health, has dramatically increased due to increasingly pervasive obesogenic lifestyle changes. Undernutrition and obesity may coexist in world regions, Countries and even smaller communities and households, being referred to as double burden of malnutrition. It is however important to point out that fat accumulation and obesity may also induce additional nutritional derangements in affected individuals, both directly through metabolic and body composition changes and indirectly through acute and chronic diseases with negative impact on nutritional status. In the current narrative review, associations between fat accumulation in obesity and malnutrition features as well as their known causes will be reviewed and summarized. These include risk of loss of skeletal muscle mass and function (sarcopenia) that may allow for malnutrition diagnosis also in overweight and obese individuals, thereby introducing a new clinically relevant perspective to the obesity-related double burden of malnutrition concept. Natu2 –5. Indee2 , 7, 3, 4e groups , 6, 9.Based on the above observations, new complex nutritional challenges have emerged in recent times, with epidemiological shifts and coexistence of under- and overnutrition. The latter concept has indeed been recently described under the definition of “double burden of malnutrition”, indicating that both under- and overnutrition are commonly observed not only at global level but may indeed coexist in the same world regions and often in the same Countries and communities. Coexistence of seemingly opposite nutritional patterns may obviously partly reflect social and economic inequalities, but additional important reasons should be pointed out. In particular, enhanced life expectancy is increasing older adult population worldwide, and elderly individuals are commonly more prone to undernutrition due to multifactorial reasons that include psychological, social and health-related factors –12. EvenThe ongoing unprecedented shift in body weight paradigms is however posing larger dramatic individual, family, socio-economic and healthcare challenges . ObesityNegative obesity- and disease-related influences on skeletal muscle mass and function maintenance are summarized below. It is increasingly clear that profound alterations in skeletal muscle metabolism may occur in obesity with potential negative impact on whole body muscle mass and function , 26. Bodprimary metabolic abnormalities and insulin resistance: although a sizable portion of the obese population is not insulin resistant, a large majority of insulin resistant persons is either overweight or obese, or it presents with excess fat accumulation in the abdominal visceral compartment , 30. Subectopic muscle fat accumulation: muscle lipid accumulation commonly results in obesity from impaired adipose tissue expansion in the presence of excess lipid availability. Skeletal muscle fat accumulation is conversely closely associated with tissue and systemic insulin resistance , 48. Mecmitochondrial dysfunction: mitochondrial changes may not occur in obese individuals and become relatively common only in relatively late stages; their onset may however lead to excess ROS production resulting in oxidative stress and related complications that may exacerbate insulin resistance and directly favor muscle loss , 31, 44.stem cell dysfunction: altered muscle stem cell function with excess adipocyte differentiation  have beeIntermediate and energy metabolism changes.metabolic complications: metabolic syndrome or overt type 2 diabetes and hyperglycemia are common in insulin resistant obese individuals and their onset may exacerbate pro-oxidative and inflammatory alterations as well as mitochondrial dysfunction. These enhanced abnormalities may further promote muscle loss and functional alterations , 48;chronic disease: chronic organ failure syndromes result in enhanced inflammation and oxidative stress through various mechanisms at tissue and systemic level, thereby also synergistically promoting muscle loss and damage . Obesitysurgery: bariatric procedures are becoming increasingly common and almost invariably lead to skeletal muscle catabolism at least in the initial rapid weight loss phase characterized by profoundly negative energy balance , 58; lowComorbidities and treatment.Lifestyle and physical inactivity: low physical activity levels play a key role in the onset of obesity and physical activity is commonly further progressively reduced with disease duration, aging and increased body weight, with direct negative impact on muscle protein turnover as well as muscle fitness . ObesityBased on the above observations, a multifactorial cluster of obesity-induced or obesity–associated alterations leads to skeletal muscle loss and dysfunction with low muscle strength and endurance, that are likely caused at least in part by low muscle mass, mitochondrial dysfunction with altered bioenergetics and fat accumulation with reduced muscle density. These changes become progressively more likely in patients with longer obesity duration, complications and older age, that may be per se independently associated with muscle loss and dysfunction.Skeletal muscle changes in obesity have a profound clinical impact. Obese individuals with low muscle mass and function have higher risk of developing frailty and disability, and may generally present with poorer quality of life. Importantly, low or declining muscle mass is emerging as a negative prognostic factor associated with higher morbidity and mortality in obese patients with various chronic complications and diseases and in aging , 64, 65.The potential relevance of muscle mass maintenance as a priority therapeutic target in obesity is regrettably hampered by inadequate awareness. Definition and diagnosis of this condition are problematic. Definition of sarcopenic obesity may combine obesity with the geriatric concept of primary sarcopenia, a combination of low muscle mass and function (particularly strength) that almost invariably occurs in old age. While diagnostic criteria for aging-associated primary sarcopenia have been proposed , they arOverall, despite relevant practical limitations, recognizing skeletal muscle depletion or dysfunction in obese individuals by body composition measurement techniques, strength measurement or other functional tests should be a priority to alert clinicians to enhanced risk for negative outcome –78.Routine nutritional screening to identify patients at risk for malnutrition is recommended in most chronic and acute disease conditions and in hospitalized patients. Validated and widely utilized screening tools include Nutritional Risk Screening-2002 (NRS-2002) . ImportaMost importantly, major guidelines have started to take nutritional needs of obese patients into account with specific recommendations for nutritional support that may combine a limitation in calorie with high protein administration aimed at preventing loss of skeletal muscle mass and function , 86. PreIn conclusion, the ongoing obesity epidemics, along with population aging and increased chronic disease prevalence is profoundly modifying fundamental clinical nutrition and healthcare priorities worldwide. A true double burden of malnutrition exists beyond coexistence of obesity and undernutrition in Countries and communities. Indeed individuals with obesity may present with true malnutrition due to inability to preserve body composition and performance with loss of skeletal muscle loss and function that exert major negative influences on morbidity and survival. Recognition of this new double burden is a relevant priority in order to more effectively identify diagnostic and therapeutic tools.


Isolated coronary Takayasu arteritis is a rare form of ischemic heart disease that typically appears as an aorto-ostial lesion. Although several vascular imaging modalities including ultrasonography, computed tomographic angiography, magnetic resonance angiography or catheter angiography, play crucial roles for diagnosing Takayasu arteritis, the intravascular ultrasound imaging of Takayasu arteritis is not well studied.A 55-year-old woman who was diagnosed with heterozygous familial hypercholesterolemia underwent coronary angiography due to effort angina, which showed ostial left anterior descending coronary artery (LAD) stenosis. Although directional coronary atherectomy followed by drug-coated balloon was successfully performed, 6 months later restenosis occurred at the ostial LAD, and the ostial left circumflex coronary artery (LCx) progressed significantly. The intravascular ultrasound imaging in these lesions was noteworthy, in which the media was partly unrecognizable and an echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia, thereby causing the whole image of the coronary artery to become unclear. Directional coronary atherectomy followed by drug-coated balloon procedures for both LAD and LCx lesions were performed again. Systemic examination of computed tomographic angiography found no other stenotic lesions except for those in the coronary arteries. Five months later, the LAD and LCx lesions progressed diffusely, therefore the coronary artery bypass graft was done. The histopathological findings of specimens of the coronary artery that were obtained during the bypass graft showed excessive fibrous thickening of the intima and adventitia, with granulomatous inflammation in the media, which led to the diagnosis of isolated coronary Takayasu arteritis. Systemic corticosteroid therapy was then started.We described an extremely rare case of isolated and non aorto-ostial Takayasu arteritis. The characteristic intravascular ultrasound images of diseased coronary arteries may help in the diagnosis of coronary Takayasu arteritis. Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, predominantly prevalent among young women . CoronarA 55-year-old woman was referred to our hospital because of chest pain on effort that had worsened in the last 3 months. The patient had no significant past medical history and was not on any medication. Family history revealed that her mother was diagnosed as having stable angina pectoris at 70. The patient had no evident physical findings of fever, lymphadenopathy, joint pain or left-right deference of blood pressure. Electrocardiogram showed regular sinus rhythm and no significant abnormalities Fig. . The echPercutaneous coronary intervention with coronary plaque atherectomy using directional coronary atherectomy (DCA) catheter  followed by paclitaxel-coated balloon  was performed on the LAD lesion, and plain old balloon angioplasty was performed on the high lateral branch lesion Fig. c and d. Five months later, she suffered from chest pain on effort again and coronary angiography showed a restenosis of the ostial LAD, as well as a stenosis of the distal left main coronary artery (LMCA) and the ostial LCx Fig. e and f. Single photon emission computed tomography myocardial perfusion imaging at 6 months after the second coronary intervention revealed significant apical and lateral wall ischemia. Coronary angiography showed the restenosis of the ostial LCx and the diffuse stenotic progressions of the mid LAD and LCx  was then started. Since the administration of corticosteroids, at the time of writing, the patient has been free from chest pain for 1 year.Takayasu arteritis is an idiopathic chronic inflammatory arteritis characterized by stenosis, occlusion or dilatation of the aorta and its major branches, and is predominantly prevalent among young women . CoronarIVUS imaging of the lesion revealed intimal fibrotic thickening without lipid-rich plaque, in which the media was partly unrecognizable and the echo intensity similar to fibrotic intimal thickening traversed from the intima to the adventitia. The histopathologic characteristics of Takayasu arteritis are granulomatous inflammation of the media and adventitia with giant cells, diffuse productive inflammation consisting of lymphocytes and plasma cells infiltration, diffuse or nodular fibrosis accompanied by disintegration and loss of elastic fibers, and reactive intimal fibrotic thickening. These conditions caused marked intimal and adventitial fibrosis . The disDirectional coronary atherectomy is a useful method especially for bifurcated lesions . The comBoth Takayasu arteritis and familial hypercholesterolemia provoke arterial stenosis as a result of inflammatory disorder of the arterial wall; however, the correlation of these diseases is unclear , 14. TheWe here described an extremely rare case of isolated and non aorto-ostial coronary Takayasu arteritis, and IVUS images of coronary lesions in Takayasu arteritis. Characteristic IVUS images may help for diagnosing coronary arteritis.