LRP1 in GABAergic neurons is a key link between obesity and memory function.

OBJECTIVE: Low-density lipoprotein receptor-related protein-1 (LRP1) regulates energy homeostasis, blood-brain barrier integrity, and metabolic signaling in the brain. Deficiency of LRP1 in inhibitory gamma-aminobutyric acid (GABA)ergic neurons causes severe obesity in mice. However, the impact of LRP1 in inhibitory neurons on memory function and cognition in the context of obesity is poorly understood. METHODS: Mice lacking LRP1 in GABAergic neurons (Vgat-Cre; LRP1loxP/loxP) underwent behavioral tests for locomotor activity and motor coordination, short/long-term and spatial memory, and fear learning/memory. This study evaluated the relationships between behavior and metabolic risk factors and followed the mice at 16 and 32 weeks of age. RESULTS: Deletion of LRP1 in GABAergic neurons caused a significant impairment in memory function in 32-week-old mice. In the spatial Y-maze test, Vgat-Cre; LRP1loxP/loxP mice exhibited decreased travel distance and duration in the novel arm compared with controls (LRP1loxP/loxP mice). In addition, GABAergic neuron-specific LRP1-deficient mice showed a diminished capacity for performing learning and memory tasks during the water T-maze test. Moreover, reduced freezing time was observed in these mice during the contextual and cued fear conditioning tests. These effects were accompanied by increased neuronal necrosis and satellitosis in the hippocampus. Importantly, the distance and duration in the novel arm, as well as the performance of the reversal water T-maze test, negatively correlated with metabolic risk parameters, including body weight, serum leptin, insulin, and apolipoprotein J. However, in 16-week-old Vgat-Cre; LRP1loxP/loxP mice, there were no differences in the behavioral tests or correlations between metabolic parameters and cognition. CONCLUSIONS: Our findings demonstrate that LRP1 from GABAergic neurons is important in regulating normal learning and memory. Metabolically, obesity caused by GABAergic LRP1 deletion negatively regulates memory and cognitive function in an age-dependent manner. Thus, LRP1 in GABAergic neurons may play a crucial role in maintaining normal excitatory/inhibitory balance, impacting memory function, and reinforcing the potential importance of LRP1 in neural system integrity.

Prosthetics, Medicine, and Disability in Modern America: The Case of the A. A. Marks Artificial Limb Company.

Through the case of the A. A. Marks Artificial Limb Company, this article explores how the technology and business of prosthetics grew in America up to the First World War. In 1853, Amasa A. Marks established the artificial limb company A. A. Marks in New York. By the time of the First World War, the company had become the largest supplier of artificial limbs in the United States and had gained international recognition, exporting its products all over the world. Focusing on the company's growth before the war, this paper analyzes how American artificial limb makers positioned themselves between art and medicine and between surgeons and disabled customers at a time when their occupation had yet to be established as a specialized profession. From the mid-nineteenth century when the artificial limb business burgeoned to the First World War, American society went through various social and cultural changes that influenced the prosthetics industry and the perception of disability. During the Civil War, numerous soldiers were injured but survived because advancements in amputation techniques enabled surgeons to save more lives despite limb loss. The growing number of maimed veterans required more mechanical and public support for their rehabilitation. As a reconstruction project of the nation and a way to address the sense of damaged masculinity felt by injured war veterans, both Union and Confederate states approved support for providing them with artificial limbs at public expense. In postbellum America, as well as deformity and amputation, industrialization created a need for artificial limbs as the brutality of advanced weapons and unfortunate accidents involving machines and railroads increased the number of amputees. Thus during the late nineteenth century and early twentieth century, recognition of maimed bodies in public places went through a legislative and cultural transformation. The growth of artificial limb manufacturer A. A. Marks was in tune with such technological, medical, and sociocultural changes. Along with technological innovations and patents to protect these innovations, Amasa Marks devised various marketing methods and strategies through which the company secured customers and finally expanded the prosthetics market. As its customers increased, the company accumulated quantitative and qualitative data from patients' responses and interviews, and its own observations. In the late nineteenth century, George E. Marks, Amasa Marks's son and a representative of the company, analyzed customers' experiences of disability, gathering information on patterns of disability and mortality rates. Based on the company's rich experience with a large number of patient cases, George Marks advanced criticisms of surgical methods and provided second opinions on amputation surgeries. In doing so, he attempted to promote the limb maker's position from mere artisan to specialist, redefining the relationship between medicine and prosthetics and between surgeon and prosthetist. He also conveyed patients' complaints and needs to the medical men in the process, and distributed the company's findings and knowledge to surgeons and the general public by publishing treatises, articles, and manuals. Consequently, the company influenced an important epistemological turn in which the prosthetic perspective was considered prior to amputation surgery, not just as an inevitable follow-up.

"It's Taboo to Talk About It": Korean American Clergy Members' Views of Mental Health.

Korean Americans are more likely to seek guidance from church leaders than to use traditional mental health services. Through semistructured key informant interviews with 16 Christian clergy members serving later-generation Korean Americans, the authors explored clergy members' perceptions of the mental health needs of their congregants. Insights from the study suggested that communication and collaboration between mental health professionals and church leaders may be helpful in addressing the Korean American community's emotional and mental health needs.

Sex Differences in Periprocedural and Long-Term Outcomes Following Transcatheter Left Atrial Appendage Occlusion: A Systematic Review and Meta-Analysis.

BACKGROUND: Atrial fibrillation (AF) is among the most common arrhythmias associated with an increased risk of cardioembolic phenomena, including stroke. Percutaneous left atrial appendage occlusion (LAAO) has proven beneficial in reducing stroke and mortality in patients with atrial fibrillation who have contraindications to anticoagulation. However, the sex differences in outcomes following LAAO have not been studied systematically. METHODS: Electronic databases PUBMED, Embase, and Web of Science were systematically searched until March 2022 for studies evaluating patient outcomes following LAAO for AF. The primary outcomes of interest were the risks of periprocedural stroke, major bleeding, pericardial complications, and all-cause mortality. Secondary outcomes included stroke risks, major bleeding, device-related thrombus, cardiovascular and all-cause mortality on long-term follow-up. A random-effects model meta-analysis was conducted, and heterogeneity was assessed using the I-squared test. RESULTS: Sixteen studies were included in the final analysis encompassing 111,775 patients, out of which 45,441 (40.7 %) were women. Women had a significantly higher risk of peri-procedural complications including all-cause mortality [relative risk (RR), 95 % confidence intervals (CI); RR 1.94, 95 % CI 1.40-2.69], stroke [RR 1.85, 95 % CI 1.29-2.67], major bleeding [RR 1.63, 95 % CI 1.08-2.44], and pericardial events [RR 1.80, 95 % CI 1.58-2.05]. However, there were no statistically significant differences between sexes in terms of risk of stroke, major bleeding, device-related thrombus, cardiovascular and all-cause mortality on long-term follow-up. CONCLUSION: Among patients undergoing LAAO implantation, women were at higher risk of periprocedural complications than men. This risk was not significant on long-term follow-up.

Executive Summary of the 2021 International Conference of Korean Dementia Association: A Report From the Academic Committee of the Korean Dementia Association.

Recently, aducanumab, a beta amyloid targeted immunotherapy, has been approved by the US Food and Drug Administration for the treatment of Alzheimer's dementia (AD). Although many questions need to be answered, this approval provides a promising hope for the development of AD drugs that could be supported by new biomarkers such as blood-based ones and composite neuropsychological tests that can confirm pathologic changes in early stages of AD. It is important to elucidate the complexity of AD which is known to be associated with other factors such as vascular etiologies and neuro-inflammation. Through the second international conference of the Korean Dementia Association (KDA), researchers from all over the world have participated in the exchange of opinions with KDA members on the most up-to-date topics. The Academic Committee of the KDA summarizes lectures to provide the depth of the conference as well as discussions. This will be an important milestone to widen the latest knowledge in the research of AD's diagnosis, therapeutics, pathogenesis that can lead to the establishment of future directions.

Translocator Protein (18 kDa) Polymorphism (rs6971) in the Korean Population.

Background and Purpose: The expression of the 18-kDA mitochondrial translocator protein (TSPO) in the brain is an attractive target to study neuroinflammation. However, the binding properties of TSPO ligands are reportedly dependent on genetic polymorphism of the TSPO gene (rs6971). The objective of this study is to investigate the rs6971 gene polymorphism in the Korean population. Methods: We performed genetic testing on 109 subjects including patients with mild cognitive impairment, Alzheimer's disease (AD) dementia, non-AD dementia, and cognitively unimpaired participants. Magnetic resonance imaging scans and detailed neuropsychological tests were also performed, and 29 participants underwent 18F-DPA714 PET scans. Exon 4 of the TSPO gene containing the polymorphism rs6971 (Ala or Thr at position 147) was polymerase chain reaction amplified and sequenced using the Sanger method. The identified rs6971 genotype codes (C/C, C/T, or T/T) of the TSPO protein generated high-, mixed-, or low-affinity binding phenotypes (HABs, MABs, and LABs), respectively. Results: We found that 96.3% of the study subjects were HAB (105 out of 109 subjects), and 3.7% of the subjects were MAB (4 out of 109 subjects). 18F-DPA-714 PET scans showed nonspecific binding to the thalamus and brainstem, and increased tracer uptake throughout the cortex in cognitively impaired patients. The participant with the MAB polymorphism had a higher DPA714 signal throughout the cortex. Conclusions: The majority of Koreans are HAB (aprox. 96%). Therefore, the polymorphism of the rs6971 gene would have a smaller impact on the availability of second-generation TSPO PET tracers.

Dr. James Smith's Dream of Eradicating Smallpox and the National Vaccine Institution.

This article re-examines from a new perspective the efforts of James Smith (1771-1841), a Maryland doctor, to eradicate smallpox in the United States. As one of the few successful cowpox inoculators at the turn of the nineteenth century, Smith recognized the necessity for a public vaccine institution that could ensure the safe production and continuous preservation and circulation of vaccine matter. Thus, he devoted himself to creating statewide and national vaccine institutions funded by the state and federal governments. He established the National Vaccine Institution (NVI), but despite his efforts, the NVI existed only a short time from 1813 to 1822. Previous studies on Smith have focused on the 1813 Vaccination Act (An Act to Encourage Vaccination) and the NVI, and have evaluated them as failed projects or historically missed opportunities. However, this kind of approach does not justly place the act and institutions within Smith's larger plan and do not fully discuss the role of the NVI in his system of promoting vaccination in the United States. This article analyzes how he responded to the problems hindering cowpox vaccination, including spurious vaccine, failed vaccination, and low public acceptance of cowpox vaccine. In doing so, this study shows that Smith attempted to establish a universal and systematic vaccination system connecting citizens, government, and medical personnel through the NVI, as well as ensuring a safe and regular supply of vaccine.

Meta-Analysis of Gender Disparities in In-hospital Care and Outcomes in Patients with ST-Segment Elevation Myocardial Infarction.

Gender disparities in ST-segment elevation myocardial infarction (STEMI) outcomes continue to be reported worldwide; however, the magnitude of this gap remains unknown. To evaluate gender-based discrepancies in clinical outcomes and identify the primary driving factors a global meta-analysis was performed. Studies were selected if they included all comers with STEMI, reported gender specific patient characteristics, treatments, and outcomes, according to the registered PROSPERO protocol: CRD42020161469. A total of 56 studies (705,098 patients, 31% females) were included. Females were older, had more comorbidities and received less antiplatelet therapy and primary percutaneous coronary intervention (PCI). Females experienced significantly longer delays to first medical contact (mean difference 42.5 min) and door-to-balloon time (mean difference 4.9 min). In-hospital, females had increased rates of mortality (odds ratio [OR] 1.91, 95% confidence interval [CI] 1.84 to 1.99, p <0.00001), repeat myocardial infarction (MI) (OR 1.25, 95% CI 1.00 to 1.56, p=0.05), stroke (OR 1.67, 95% CI 1.27 to 2.20, p <0.001), and major bleeding (OR 1.82, 95% CI 1.56 to 2.12, p <0.00001) compared with males. Older age at presentation was the primary driver of excess mortality in females, although other factors including lower rates of primary PCI and aspirin usage, and longer door-to-balloon times contributed. In contrast, excess rates of repeat MI and stroke in females appeared to be driven, at least in part, by lower use of primary PCI and P2Y12 inhibitors, respectively. In conclusion, despite improvements in STEMI care, women continue to have in-hospital rates of mortality, repeat MI, stroke, and major bleeding up to 2-fold higher than men. Gender disparities in in-hospital outcomes can largely be explained by age differences at presentation but comorbidities, delays to care and suboptimal treatment experienced by women may contribute to the gender gap.

Recent progress in development and applications of second near-infrared (NIR-II) nanoprobes.

Optical probes for near-infrared (NIR) light have clear advantages over UV/VIS-based optical probes, such as their low levels of interfering auto-fluorescence and high tissue penetration. The second NIR (NIR-II) window (1000-1350 nm) offers better light penetration, lower background signal, higher safety limit, and higher maximum permitted exposure than the first NIR (NIR-I) window (650-950 nm). Therefore, NIR-II laser-based photoacoustic (PA) and fluorescence (FL) imaging can offer higher sensitivity and penetration depth than was previously available, and deeper lesions can be treated in vivo by photothermal therapy (PTT) and photodynamic therapy (PDT) with an NIR-II laser than with an NIR-I laser. Advances in creation of novel nanomaterials have increased options for improving light-induced bioimaging and treatment. Nanotechnology can provide advantages such as good disease targeting ability and relatively long circulation times to supplement the advantages of optical technologies. In this review, we present recent progress in development and applications of NIR-II light-based nanoplatforms for FL, PA, image-guided surgery, PDT, and PTT. We also discuss recent advances in smart NIR-II nanoprobes that can respond to stimuli in the tumor microenvironment and inflamed sites. Finally, we consider the challenges involved in using NIR-II nanomedicine for effective diagnosis and treatment.

LRP1 regulates food intake and energy balance in GABAergic neurons independently of leptin action.

Low-density lipoprotein receptor-related protein 1 (LRP1) is a member of LDL receptor family that plays a key role in systemic glucose and lipid homeostasis. LRP1 also regulates energy balance in the hypothalamus by mediating leptin's anorexigenic action, although the underlying neurocircuitry involved is still unclear. Because GABAergic neurons are a major mediator of hypothalamic leptin action, we studied the role of GABAergic LRP1 in energy balance and leptin action using mice lacking LRP1 in Vgat- or AgRP-expressing neurons (Vgat-Cre; LRP1loxP/loxP or AgRP-Cre; LRP1loxP/loxP). Here, we show that LRP1 deficiency in GABAergic neurons results in severe obesity in male and female mice fed a normal-chow diet. This effect is most likely due to increased food intake and decreased energy expenditure and locomotor activity. Increased adiposity in GABAergic neuron-specific LRP1-deficient mice is accompanied by hyperleptinemia and hyperinsulinemia. Insulin resistance and glucose intolerance in these mice are occurred without change in body weight. Importantly, LRP1 in GABAergic neurons is not required for leptin action, as evidenced by normal leptin's anorexigenic action and leptin-induced hypothalamic Stat3 phosphorylation. In contrast, LRP1 deficiency in AgRP neurons has no effect on adiposity and caloric intake. In conclusion, our data identify GABAergic neurons as a key neurocircuitry that underpins LRP1-dependent regulation of systemic energy balance and body-weight homeostasis. We further find that the GABAergic LRP1 signaling pathway modulates food intake and energy expenditure independently of leptin signaling and AgRP neurons.

Mind the gap: an intervention to support caregivers with a new autism spectrum disorder diagnosis is feasible and acceptable.

INTRODUCTION: Children with autism spectrum disorder (ASD) benefit when their caregivers can effectively advocate for appropriate services. Barriers to caregiver engagement such as provider mistrust, cultural differences, stigma, and lack of knowledge can interfere with timely service access. We describe Mind the Gap (MTG), an intervention that provides education about ASD, service navigation, and other topics relevant to families whose children have a new ASD diagnosis. MTG was developed via community partnerships and is explicitly structured to reduce engagement barriers (e.g., through peer matching, meeting flexibility, culturally-informed practices). We also present on the results of a pilot of MTG, conducted in preparation for a randomized controlled trial. METHODS: MTG was evaluated using mixed methods that included qualitative analysis and pre/post-test without concurrent comparison group. Participants (n=9) were primary caregivers of children (ages 2-7 years) with a recent ASD diagnosis and whose annual income was at or below 185% of the federal poverty level. In order to facilitate trust and relationship building, peer coaches delivered MTG. The coaches were parents of children with ASD who we trained to deliver the intervention. MTG consisted of up to 12 meetings between coaches and caregivers over the course of 18 weeks. Coaches delivered the intervention in homes and other community locations. Coaches shared information about various "modules," which were topics identified as important for families with a new ASD diagnosis. Coaches worked with families to answer questions, set weekly goals, assess progress, and offer guidance. For the pilot, we focused on three primary outcomes: feasibility, engagement, and satisfaction. Feasibility was measured via enrollment and retention data, as well as coach fidelity (i.e., implementation of MTG procedures). Engagement was measured via number of sessions attended and percentage completion of the selected outcome measures. For completers (n=7), satisfaction was measured via a questionnaire (completed by caregivers) and open-ended interviews (completed by caregivers and coaches). RESULTS: We enrolled 56% of referred caregivers and 100% of eligible families. Retention was high (78%). Coaches could deliver the intervention with fidelity, completing, on average, 83% of program components. Engagement also was high; caregivers attended an average of 85% of total possible sessions and completed 100% of their measures. Caregivers indicated moderately high satisfaction with MTG. Qualitative data indicated that caregivers and coaches were positive about intervention content, and the coach-caregiver relationship was important. They also had suggestions for changes. CONCLUSION: Mind the Gap demonstrates evidence of feasibility, and data from the pilot suggest that it addresses intervention engagement barriers for a population that is under-represented in research. The results and suggestions from participants were used to inform a large-scale RCT, which is currently underway. Overall, MTG shows promise as an intervention that can be feasibly implemented with under-resourced and ethnic minority families of children with ASD. TRIAL REGISTRATION: This study is registered with ClinicalTrials.gov: NCT03711799.

Pathogenic PSEN1 Thr119Ile Mutation in Two Korean Patients with Early-Onset Alzheimer's Disease.

We report a probable pathogenic Thr119Ile mutation in presenilin-1 (PSEN1) in two unrelated Korean patients, diagnosed with early onset Alzheimer's disease (EOAD). The first patient presented with memory decline when she was 64 years old. Magnetic resonance imaging (MRI) scans showed diffuse atrophy in the fronto-parietal regions. In addition, 18F-fludeoxyglucose positron emission tomography (FDG-PET) showed reduced tracer uptake in the parietal and temporal cortices, bilaterally. The second patient developed memory dysfunction at the age of 49, and his mother was also affected. Amyloid positron emission tomography (PET) was positive, but MRI scans did not reveal any atrophy. Targeted NGS and Sanger sequencing identified a heterozygous C to T exchange in PSEN1 exon 5 (c.356C>T), resulting in a p.Thr119Ile mutation. The mutation is located in the conserved HL-I loop, where several Alzheimer's disease (AD) related mutations have been described. Structure analyses suggested that Thr119Ile mutation may result in a significant change inside conservative loop. Additional in vitro studies are needed to estimate the role of the PSEN1 Thr119Ile in AD disease progression.

Rethinking the History of Smallpox in the Early Twentieth Century: The SS Korea and Uncertainty Surrounding the Diagnosis of Smallpox.

This research explores the case of the 1903 smallpox outbreak on the SS Korea , a transpacific carrier making runs between Southeast Asia, East Asia, Hawaii, and the United States. These regions were connected to a degree that no one had ever imagined through the SS Korea . Honolulu, Hawaii, was one of the most important territories in US maritime history and served as a waypoint between Asia and San Francisco on the mainland. As increasing numbers of people traveled by sea, various microbes were communicated across the Pacific Ocean. International tourists traveling across the ocean to Hawaii and the United States were alerted to infectious diseases, smallpox being one of the most significant of such diseases. The story of the SS Korea serves as an important lens through which to explore the early twentieth century transpacific world connected through Honolulu. Focusing on the spread of smallpox via international travelers, this research studies aspects of the public health system that were developed to contain smallpox infection on international ships and the application of smallpox vaccination as a method for infectious disease control. More importantly, in bringing attention to the uncertainty surrounding the diagnosis of smallpox, this research argues for the necessity of historians to build a more comprehensive medical historical context for disease control systems that includes the limits of medical science in making diagnoses of infectious diseases, the uncertainties arising from a lack of this component, and the implementation of health policies and preventative medical technologies.

[¹8F]THK5351 PET Imaging in Patients with Mild Cognitive Impairment.

BACKGROUND AND PURPOSE: Mild cognitive impairment (MCI) is a condition with diverse clinical outcomes and subgroups. Here we investigated the topographic distribution of tau in vivo using the positron emission tomography (PET) tracer [¹8F]THK5351 in MCI subgroups. METHODS: This study included 96 participants comprising 38 with amnestic MCI (aMCI), 21 with nonamnestic MCI (naMCI), and 37 with normal cognition (NC) who underwent 3.0-T MRI, [¹8F]THK5351 PET, and detailed neuropsychological tests. [¹8F]flutemetamol PET was also performed in 62 participants. The aMCI patients were further divided into three groups: 1) verbal-aMCI, only verbal memory impairment; 2) visual-aMCI, only visual memory impairment; and 3) both-aMCI, both visual and verbal memory impairment. Voxel-wise statistical analysis and region-of-interest -based analyses were performed to evaluate the retention of [¹8F]THK5351 in the MCI subgroups. Subgroup analysis of amyloid-positive and -negative MCI patients was also performed. Correlations between [¹8F]THK5351 retention and different neuropsychological tests were evaluated using statistical parametric mapping analyses. RESULTS: [¹8F]THK5351 retention in the lateral temporal, mesial temporal, parietal, frontal, posterior cingulate cortices and precuneus was significantly greater in aMCI patients than in NC subjects, whereas it did not differ significantly between naMCI and NC participants. [¹8F] THK5351 retention was greater in the both-aMCI group than in the verbal-aMCI and visualaMCI groups, and greater in amyloid-positive than amyloid-negative MCI patients. The cognitive function scores were significantly correlated with cortical [¹8F]THK5351 retention. CONCLUSIONS: [¹8F]THK5351 PET might be useful for identifying distinct topographic patterns of [¹8F]THK5351 retention in subgroups of MCI patients who are at greater risk of the progression to Alzheimer's dementia.

A Historiographical Review of the History of Western Medicine, 2011-2020 The Diversification of Subject Matter and the Search for a New Methodology.

This article examines major issues in the historiography of Western medical history between 2011 and 2020 through an analysis of scholarly articles published in journals based in the United States, Britain, and South Korea. The subject matter and methodology of the history of medicine in the West have greatly transformed since the start of the second millennium, from biographical history to historicism to social history to intellectual and cultural history. Through this process, the definition of "medicine" has been continuously denaturalized and expanded, and so have the topics its scholars deal with. Having a variety of perspectives and keeping their disciplinary boundaries porous, historians of Western medical history have examined issues of health, disease, and medicine. They have also vigilantly pursued advancements in methodology for historical analysis, experimented with different writing styles, and expanded historical resources, including visual and audio records. In recent decades, the history of medicine has seen additional experimentation with the changing understanding of the relationship between medicine and society, especially with the emergence of a knowledge- and information-based society and globalization. Furthermore, historians have attempted to establish the value of the history of medicine in response to changing perceptions of medicine and history in the twenty-first century. Their efforts have vitalized the field of medical history by treating it as a useful lens for observing medicine's past as well as formulating critical questions about its present.

Relationships between [¹8F]-THK5351 Retention and Language Functions in Primary Progressive Aphasia.

BACKGROUND AND PURPOSE: There are three distinct subtypes of primary progressive aphasia (PPA): the nonfluent/agrammatic variant (nfvPPA), the semantic variant (svPPA), and the logopenic variant (lvPPA). We sought to characterize the pattern of [¹8F]-THK5351 retention across all three subtypes and determine the topography of [¹8F]-THK5351 retention correlated with each neurolinguistic score. METHODS: We enrolled 50 participants, comprising 13 PPA patients (3 nfvPPA, 5 svPPA, and 5 lvPPA) and 37 subjects with normal cognition (NC) who underwent 3.0-tesla magnetic resonance imaging, [¹8F]-THK5351 positron-emission tomography scans, and detailed neuropsychological tests. The PPA patients additionally participated in extensive neurolinguistic tests. Voxel-wise and region-of-interest-based analyses were performed to analyze [¹8F]-THK5351 retention. RESULTS: The nfvPPA patients exhibited higher [¹8F]-THK5351 retention in the the left inferior frontal and precentral gyri. In svPPA patients, [¹8F]-THK5351 retention was elevated in the anteroinferior and lateral temporal cortices compared to the NC group (left>right). The lvPPA patients exhibited predominant [¹8F]-THK5351 retention in the inferior parietal, lateral temporal, and dorsolateral prefrontal cortices, and the precuneus (left>right). [¹8F]-THK5351 retention in the left inferior frontal area was associated with lower fluency scores. Comprehension was correlated with [¹8F]-THK5351 retention in the left temporal cortices. Repetition was associated with [¹8F]-THK5351 retention in the left inferior parietal and posterior temporal areas, while naming difficulty was correlated with retention in the left fusiform and temporal cortices. CONCLUSIONS: The pattern of [¹8F]-THK5351 retention was well matched with clinical and radiological findings for each PPA subtype, in agreement with the anatomical and functional location of each language domain.

Role of POMC and AgRP neuronal activities on glycaemia in mice.

Leptin regulates both feeding and glycaemia primarily through its receptors expressed on agouti-related peptide (AgRP) and pro-opiomelanocortin-expressing (POMC) neurons; however, it is unknown whether activity of these neuronal populations mediates the regulation of these processes. To determine this, we injected Cre-dependent designer receptors exclusively activated by designer drugs (DREADD) viruses into the hypothalamus of normoglycaemic and diabetic AgRP-ires-cre and POMC-cre mice to chemogenetically activate or inhibit these neuronal populations. Despite robust changes in food intake, activation or inhibition of AgRP neurons did not affect glycaemia, while activation caused significant (P = 0.014) impairment in insulin sensitivity. Stimulation of AgRP neurons in diabetic mice reversed leptin's ability to inhibit feeding but did not counter leptin's ability to lower blood glucose levels. Notably, the inhibition of POMC neurons stimulated feeding while decreasing glucose levels in normoglycaemic mice. The findings suggest that leptin's effects on feeding by AgRP neurons are mediated by changes in neuronal firing, while the control of glucose balance by these cells is independent of chemogenetic activation or inhibition. The firing-dependent glucose lowering mechanism within POMC neurons is a potential target for the development of novel anti-diabetic medicines.

Recent advances in the treatment of C. difficile using biotherapeutic agents.

Clostridium difficile (C. difficile) is rapidly becoming one of the most prevalent health care-associated bacterial infections in the developed world. The emergence of new, more virulent strains has led to greater morbidity and resistance to standard therapies. The bacterium is readily transmitted between people where it can asymptomatically colonize the gut environment, and clinical manifestations ranging from frequent watery diarrhea to toxic megacolon can arise depending on the age of the individual or their state of gut dysbiosis. Several inexpensive approaches are shown to be effective against virulent C. difficile in research settings such as probiotics, fecal microbiota transfer and immunotherapies. This review aims to highlight the current advantages and limitations of the aforementioned approaches with an emphasis on recent studies.

Correction to: Caregiver Voices: Cross-Cultural Input on Improving Access to Autism Services.

Please note that the middle name of coauthor Francisco Reinosa Segovia was misspelled (as "Rienosa") is this article as originally published.

Examining relationships between child skills and potential key components of an evidence-based practice in ASD.

BACKGROUND: Research in autism spectrum disorders (ASD) has identified a need to understand key components of complex evidence-based practices (EBP). One approach involves examining the relationship between component use and child behavior. AIMS: This study provides initial evidence for identifying key components in a specific EBP, Pivotal Response Training (PRT). We examined which components were related to child response and evaluated relationships between provider characteristics, child characteristics and component intensity. METHODS: Trained coders reviewed archival videos (n = 278) for PRT fidelity and child behavior. We completed multi-level regression and latent profile analysis to examine relationships between intensity of individual or combinations of PRT components and child behavior, and moderators of component use. RESULTS: Analyses indicated differential relationships between specific components and child behaviors which may support methods of altering intensity of components to individualize intervention. Profile analysis suggested relatively intensive use of most PRT components, especially antecedent strategies, may maximize child responsivity. Providers with postgraduate education trended toward higher intensity component use. Child characteristics did not moderate use. IMPLICATIONS: Careful examination of key components of ASD interventions may helps clarify the mechanisms of action. Recommendations specific to PRT implementation and use of the methodology for other interventions are discussed.