Corneal confocal microscopy (CCM) examination revealed a reduction of corneal small fiber sensory nerve number and branching in ALS patients. Quantitative analysis demonstrated an increase in tortuosity and reduction in length and fractal dimension of ALS patients’ corneal nerve fibers compared to age-matched controls. Moreover, bulbar function disability scores were significantly related to measures of corneal nerve fibers anatomical damage. Our study demonstrates for the first time a corneal small fiber sensory neuropathy in ALS patients. This finding further suggests a link between sporadic ALS and facial-onset sensory and motor neuronopathy (FOSMN) syndrome, a rare condition characterized by early sensory symptoms , followed by wasting and weakness of bulbar and upper limb muscles. In addition, the finding supports a model of neurodegeneration in ALS as a focally advancing process.Although subclinical involvement of sensory neurons in amyotrophic lateral sclerosis (ALS) has been previously demonstrated, corneal small fiber sensory neuropathy has not been reported to-date. We examined a group of sporadic ALS patients with corneal confocal microscopy, a recently developed imaging technique allowing  Corneal confocal microscopy has a number of comparative advantages over previous techniques such as skin biopsy, allowing non invasive, potentially repeatable and quantitative analysis of small sensory fibers at the microscopic level  is a fatal disorder primarily characterized by progressive degeneration of upper (UMN) and lower motor neurons (LMN), in the brain and spinal cord  = 5 years) were recruited consecutively, upon obtaining written informed consent. Seven age-matched healthy individuals served as controls  and the sub-basal nerve plexus was imaged, as previously described .Between group differences were assessed with the Mann-Whitney test. In ALS patients, correlation between clinical and CCM data was investigated with Spearman’s rank correlation (r). Statistical significance was considered at −1) compared with controls . These data suggest that a corneal sensory neuropathy exists in ALS patients. Amyotrophic lateral sclerosis-Functional Rating Scale-bulbar score was significantly related to CNL  and CNFD ; coherently, ALS-SS-bulbar score was significantly related to both CNL  and CNFD   Figure , Table 2Our study demonstrates for the first time a corneal small fiber sensory neuropathy in sporadic ALS patients, consistent with previous clinical, pathological and neurophysiological studies showing subclinical sensory neuron involvement in this disease and confirming that neurodegeneration exceeds the neuronal system upon which clinical diagnosis relies  involvement in sporadic ALS, contributing to the understanding of the pathomechanisms of this disease.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.


Skeletal muscle physiology is influenced by the presence of chemically reactive molecules such as reactive oxygen species (ROS). These molecules regulate multiple redox-sensitive signaling pathways that play a critical role in cellular processes including gene expression and protein modification. While ROS have gained much attention for their harmful effects in muscle fatigue and dysfunction, research has also shown ROS to facilitate muscle adaptation after stressors such as physical exercise. This manuscript aims to provide a comprehensive review of the current understanding of redox signaling in skeletal muscle. ROS-induced oxidative stress and its role in the aging process are discussed. Mitochondria have been shown to generate large amounts of ROS during muscular contractions, and thus are susceptible to oxidative stress. ROS can modify proteins located in the mitochondrial membrane leading to cell death and osmotic swelling. ROS also contribute to the necrosis and inflammation of muscle fibers that is associated with muscular diseases including Duchenne muscular dystrophy. It is imperative that future research continues to investigate the exact role of ROS in normal skeletal muscle function as well as muscular dysfunction and disease. Current research is revealing new perspectives regarding the biological significance of free radicals and other chemically reactive molecules in numerous physiological processes and pathological conditions. Reactive oxygen species (ROS), when generated in excess amounts, contribute to oxidative stress. ROS produced from contracting skeletal muscle are known to affect both muscle adaption and function  can be produced within skeletal muscle fibers from L-arginine by NO• synthase (NOS). Three major isoforms of NOS exist: neuronal NOS (nNOS or NOS I); inducible NOS (iNOS or NOS II); and endothelial NOS (eNOS or NOS III)  , which is a potent oxidizing agent  via superoxide dismutases (SOD). However, H2O2 can, in turn, form highly reactive hydroxyl radicals (•OH) through a Fenton reaction  pathway. ONOOIncreases in ROS production are generated through a variety of signaling mechanisms. For example, interleukin (IL)-13 plays a critical role in the immune system maintaining normal homeostasis as well as responding to pathogens   , and calcineurin all play a marked role in adaptation to events including exercise training  affect mtDNA more extensively than nuclear DNA   Table  (Barbierc) Table . ROS indc) Table  (Barbierc) Table . Accordic) Table .Since neurons continuously generate free radicals, a sufficient supply of endogenous antioxidants is necessary to maintain homeostasis (Galea et al., 2+ associated with muscular dystrophy (Table ROS are involved in the modulation of skeletal muscle contractions (Zuo et al., hy Table  (Bellinghy Table . ROS oxihy Table  (Goldstehy Table .The research reviewed in this article has identified many of the reactive species that affect skeletal muscle function. The pathways mediated by ROS/RNS signaling have been discussed as well as their role in skeletal muscle physiology. ROS have both beneficial and harmful effects on skeletal muscle function as they are ubiquitously involved in gene expression, immune responses, mitochondrial oxidative stress, skeletal muscle atrophy, as well as neuromuscular dystrophies. Redox-sensitive pathways continue to be an area of much needed research. Such studies in the future will shed significant insight into the exact role of ROS in health and disease.LZ designed the outline of the paper and wrote the paper; BP wrote the paper.This work was supported by OSUCOM-HRS Fund 013000.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.


The Affordable Care Act and the Medicaid redesign in New York City offer opportunities to explore alternative methods for measuring the effectiveness of behavioral health interventions. Quality of life (QOL) measures have been underutilized in substance use disorders treatment (SUDT). The objective of this study was to determine how a validated QOL instrument could be used in SUDT as a measure of health-related patient outcomes.t-tests. We examined change in QOL scores among OTP participants stratified by major health conditions.NYC outpatient drug treatment (DT) and opioid treatment programs (OTP) were invited to participate in a pilot evaluation. Newly admitted patients completed counselor-administered surveys at admission, and 90 and 180 days. Surveys included demographic  and clinical items  in addition to the World Health Organization QOL instrument, the WHOQOL-BREF ; scoringBetween July and September 2013, 1269 newly admitted patients were surveyed. Follow-up surveys were completed for 616 patients at 90 days (49%) and 336 at 180 days (26%). See Table Preliminary findings indicate that individuals in SUDT have lower QOL scores than healthy populations and experience improvements in QOL during treatment. Small positive changes among individuals with health conditions suggest the importance of integrating physical health care with SUDT. High dropout rates, multiple survey administrators, and an English-only survey instrument may limit our conclusions. Future investigations need to examine the feasibility of incorporating QOL measures into SUDT more broadly, including its impact on clinical interventions and longer-term patient outcomes, including maintenance of QOL gains achieved during SUDT.


Telomeres are dynamic nucleoprotein structures that protect the ends of chromosomes from degradation and activation of DNA damage response. For this reason, telomeres are essential to genome integrity. Chromosome ends are enriched in heterochromatic marks and proper organization of telomeric chromatin is important to telomere stability. Despite their heterochromatic state, telomeres are transcribed giving rise to long noncoding RNAs (lncRNA) called TERRA (telomeric repeat-containing RNA). TERRA molecules play critical roles in telomere biology, including regulation of telomerase activity and heterochromatin formation at chromosome ends. Emerging evidence indicate that TERRA transcripts form DNA-RNA hybrids at chromosome ends which can promote homologous recombination among telomeres, delaying cellular senescence and sustaining genome instability. Intriguingly, TERRA RNA-telomeric DNA hybrids are involved in telomere length homeostasis of telomerase-negative cancer cells. Furthermore, TERRA transcripts play a role in the DNA damage response (DDR) triggered by dysfunctional telomeres. We discuss here recent developments on TERRA's role in telomere biology and genome integrity, and its implication in cancer. Telomeres are nucleoprotein structures assembled at the extremities of eukaryotic chromosomes that protect chromosome ends. By doing so, telomeres prevent chromosome ends from being recognized as sites of DNA damage, protecting them from degradation and inappropriate recombination events due to erroneous activation of DNA repair pathways  followed by a single-stranded G-rich 3′ overhang. Electron microscopy and super-resolution fluorescence imaging have shown that telomeric DNA forms higher order structures where the 3′ single-stranded overhang invades the homologous double-stranded region forming a telomeric loop (T-loop)  pathway or members of the heterogeneous nuclear ribonucleoprotein family (hnRNPs) which bind TERRA, increases localization of TERRA at chromosome ends without affecting its overall levels or stability    is bound by the ssDNA binding protein RPA which is required for activation of the ATR checkpoint .Telomerase is an established key target for cancer therapies Harley, . Yet recThe 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.


Compounds containing guanidine-related molecules have been used since medieval times to relieve symptoms of diabetes mellitus. Guanidine itself was too toxic but two linked guanidine rings (biguanides) were useful and generally safer. For 20 years, phenformin was used before adverse effects led to removal from the US and European markets. Metformin continues to be widely prescribed for diabetes treatment and is associated with improved survival compared to other diabetes drugs. With the current interest in using the more potent phenformin for cancer therapy, it is timely to review the risks, benefits, and potential contraindications.Nnmt). NNMT methylates nicotinamide (vitamin B3) using S-adenosylmethionine (SAM) as a methyl donor. Nicotinamide is a precursor for NAD+, an important cofactor linking cellular redox states with energy metabolism. NNMT expression is increased in adipose tissue and liver of obese and diabetic mice. Furthermore, NNMT knockdown in adipose tissue and liver using anti-sense oligonucleotides in mice on a high fat diet, protects against diet-induced obesity by augmenting cellular energy expenditure. This involves a novel mechanism which could provide new strategies for prevention and treatment of obesity and type 2 diabetes. Since NNMT is also elevated in many cancers, NNMT knockdown could be beneficial for cancer prevention and/or treatment.The adipose cell is as an endocrine organ in addition to its role in energy storage. Adipocytes secrete hormones, cytokines and other factors that influence energy balance, glucose homeostasis, insulin sensitivity and vascular biology. In humans with obesity and type 2 diabetes, expression of the Glut4 glucose transporter is down-regulated selectively in adipocytes resulting in systemic insulin resistance. Knocking out Glut4 selectively in adipocytes in mice increases the risk of diabetes while adipose-specific Glut4 overexpression confers enhanced glucose tolerance in spite of increased adiposity. To understand how adipocytes regulate glucose homeostasis and insulin sensitivity, we performed DNA microarray analysis of adipose tissue from mice with adipose-specific knockdown or overexpression of Glut4. The most highly reciprocally regulated gene is nicotinamide N-methyltransferase (


Genome duplication is temporarily coordinated with sister chromatid cohesion and DNA damage tolerance. Recently, we found that replication fork-coupled repriming is important for both optimal cohesion and error-free replication by recombination. The mechanism involved has implications for the etiology of replication-based genetic diseases and cancer. To maintain genome stability, chromosome replication must faithfully preserve genome content in an optimal chromatin structural context. This requirement is met by temporal coordination of DNA replication with DNA damage tolerance (DDT), which promotes completion of replication, and with pathways associated with chromosome structural integrity, such as sister chromatid cohesion (SCC).et al., we report that replicative helicase-coupled repriming is important for efficient error-free replication by template switching, thus preventing the high levels of mutagenesis and faulty strand-annealing events associated with genome rearrangements.Chromosome replication is carried out by the replisome machinery, which is initially assembled at replication origins.Cohesin is essential for SCC establishment during DNA replication.First, our study indicates that error-free replication following genotoxic stress is greatly influenced by replication fork-coupled repriming. When this repriming function is compromised, DNA metabolism events that are kinetically disfavored in wild-type cells and involve fork reversal and genome rearrangements become more frequent . The relThe repriming conditions that we recently described are not only associated with defective error-free DDT and altered replication fork architecture, but also negatively influence SCCNo potential conflicts of interest were disclosed.


Human tumours typically harbour multiple mutations in tumour suppressor genes and oncogenes. Histologically identical tumours in different patients often exhibit different combinations of genetic alterations and it is now also evident that considerable genetic heterogeneity can exist between cells within individual tumours. A major ongoing research challenge remains to determine the functional significance of this enormous genetic diversity and heterogeneity in terms of impact on tumour phenotypes and responses to therapies. Autochthonous mouse models of human tumours have provided many insights into the combinations of genetic alterations that are causal to tumour initiation and progression in different tissues. However, conventional germline-based genetic approaches, such as the generation of compound mutant mice based on transgenics and knockouts, are limited by the time and cost associated with extensive intercrossing of mouse lines. Faster and more powerful genetic tools are required to accelerate the functional annotation of cancer mutational cataloguing studies. Excitingly, several new viral vector-mediated genetic approaches offer the ability to directly modify the genome of somatic cells in mouse tissues and these have recently been applied to the rapid generation of complex mouse tumour models that harbour multiple genetic changes.Trp53 and Nf1 or that co-express oncogenic Hras and shRNA against Trp53 were employed to generate autochthonous mouse models of glioma [http://www.addgene.org/kits/mule-system/) that provides a highly flexible genetic toolbox allowing combinatorial gene knockdown, knockout, mutation or overexpression, together with tagging of infected cells with useful markers such as luciferase or fluorescent proteins [Hras and shRNAs against Cdkn2a or Trp53 or against both Trp53 and Pten, induced the formation of pleomorphic sarcomas that could be quantitatively monitored using luciferase-based imaging [Trp53 and activation of oncogenic Kras in germline-modified mice [The use of lentiviral gene delivery vectors for cancer modelling studies offers the advantage that the proviral DNA integrates into the genome of infected cells, providing heritability of the introduced genetic alterations. Injections of lentiviruses that co-express shRNAs against proteins . We demoied mice , validatTrp53, Lkb1 and Kras, together with a template for homology directed repair to insert an oncogenic Kras mutant into the endogenous locus, allowed the generation of lung tumours driven by three different genetic mutations [Trp53 and oncogenic Kras alleles provided a series of lung cancer models with complex genetic backgrounds [Eml4-Alk chromosomal rearrangement [Several genetically complex lung cancer models in mice have recently been generated using different types of viral vectors. Adenovirus and Adeno-associated virus (AAV) DNA remains episomal in infected mouse cells and is lost by dilution upon repeated cell division, which has historically limited the use of these vectors in tumour modelling. However, in the context of the CRISPR/Cas9 system, the episomal nature of viral infection is in fact advantageous as the introduced viral DNA represents a template that can be used for homology directed repair following Cas9-induced DNA double strand breakage. Taking advantage of transgenic mice expressing Cre-activatable Cas9, the intratracheal delivery of AAV9 viruses expressing Cre, luciferase, sgRNAs against kgrounds . Finallyangement .in vivo screens based on combinatorial genetics and will potentially allow experiments that better mimic intratumoural genetic heterogeneity. These new genetic tools will assist researchers in tackling the challenges of understanding the functional implications of the genetic complexities of human malignancies.These studies collectively highlight the new genetic power that is offered by the use of viral vector-mediated somatic genetics in wild type or germline modified mice. By employing different types of lentiviral, retroviral, adenoviral and AAV vectors, together with the use of cell-type specific promoters or infection of germline-modified mice that allow cell type-specific Cre, tTA or rtTA expression, it should be possible to specifically direct genetic modulations to diverse somatic cell types. The ability to clone libraries (eg. shRNA or sgRNA) into these viral expression vectors will pave the way for


Neck dissection has traditionally played an important role in the management of patients with regionally advanced head and neck squamous cell carcinoma (HNSCC) treated with radical radiotherapy alone. However, with the incorporation of chemotherapy in the therapeutic strategy for advanced HNSCC and resultant improvement in outcome the routine use of post chemo-radiotherapy neck dissection is being questioned.Published data for this review was identified by systematically searching MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language.There is lack of high quality evidence on the role of planned neck dissection in advanced HNSCC treated with chemo-radiotherapy. A systematic literature search could identify only one small randomized controlled trial (Level I evidence) addressing this issue, albeit with major limitations. Upfront neck dissection followed by chemo-radiotherapy resulted in better disease-specific survival as compared to chemoradiation only. Several single arm prospective and retrospective reports were also identified with significant heterogeneity and often-contradictory conclusions.Planned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. Unless there are better non-invasive ways to identify residual viable disease, the role of such neck dissection shall remain debatable. A large randomized controlled trial addressing this issue is needed to clarify its role and provide evidence-based answers. The optimal management of the neck in loco-regionally advanced head & neck squamous cell carcinomas (HNSCC) following primary chemo-radiotherapy remains controversial ,2. TradiPublished data for this review was identified by systematically searching the MEDLINE, CANCERLIT & EMBASE databases from 1995 until date with restriction to the English language. "Head & Neck cancer" OR "HNSCC" was combined with "chemo-radiotherapy" OR "chemo-radiation" as Medical Subject Heading (MeSH) terms and each of the following phrase used as text words: "adjuvant neck dissection"; "planned neck dissection"; and "neck management". Relevant cross-references were also considered.There is only one small randomized control trial (American Society of Clinical Oncology  Level I In absence of high quality evidence, the best available evidence tempered with clinical judgment often guides decision-making. Two of the recently published reports ,12 somewArgiris  et al evBrizel  et al idApart from the afore-mentioned two reports, there are a few reasonably large studies (involving >50 patients: Table The potential benefit of planned neck dissection after a course of intensive chemo-radiotherapy in terms of improved regional control with or without an impact on survival needs to be weighed against the expected morbidity associated with the surgical procedure ,14,25. OPlanned neck dissection after radical chemo-radiotherapy achieves a high level of regional control, but its ultimate benefit is limited to a small subset of patients only. The morbidity of such dissection is small, but significant. Its impact on survival is yet to be completely realized. In the majority of patients it is either unnecessary because there is no residual disease in the neck or futile because of unsalvageable primary recurrence or distant metastases. Nevertheless, it is recommended that planned neck dissection be performed for patients with less than a complete response in the neck after combined modality therapy to optimize regional control, provided the primary is controlled and there is no evidence of distant metastases. It should also be performed as part of salvage surgery for locally persistent or residual disease at primary site. The criterion for planned neck dissection for patients with advanced nodal disease with a CCR in the neck following chemo-radiotherapy should incorporate not only the nodal staging but also the actual size of the involved lymph nodes. Unless there are better non-invasive ways to identify residual viable disease, which could include functional imaging like Positron Emission Tomography and biological assays like hypoxia markers, the role of such neck dissection shall remain debatable. A large randomized controlled trial across several institutions addressing these issues is needed to clarify the role of planned neck dissection in advanced HNSCC treated with primary chemo-radiotherapy and provide evidence-based answers.No source of funding involved in this reviewNone declared.Dr JP proposed the idea of systematic review on the issueDr TG did the literature search & prepared the manuscriptDr JP critically reviewed and revised the manuscript


These newer options and various anti-tumor necrosis factor (anti-TNF) therapies are used as either first-line therapy or as an option when therapy is switched.The rising direct health care costs over the past 10 years attributable to Inflammatory Bowel Disease (IBD) is largely driven by expenditures on biological medications.non-medical switching or discontinuation of anti-TNF therapies is associated with worse clinical outcomes and increased health care resource utilization.2 In addition, uncontrolled moderate to severe IBD leads to a negative impact on the quality of life, work productivity, and increased risk for IBD-related surgeries and hospitalizations.3With an appropriate emphasis on value-based health care, cost implications of managing complex IBD patients are becoming increasingly important. However, Measuring validated clinical outcomes or surrogate markers of clinical outcomes whiles on different biologic therapies with different costs provides some guidance for cost-effective management in IBD.CC360, Chiorean et al report their findings on healthcare resource utilization and associated costs in a cohort of IBD patients switching to a second biologic agent. Their retrospective study titled “Economic Outcomes of Inflammatory Bowel Disease Patients Switching to a Second Anti-Tumor Necrosis Factor or Vedolizumab” lends some insight to costs implications versus outcomes of switching out of class in patients failing initial anti-TNF agents.In this issue of fewer all-cause and IBD-related outpatient visits.The total and treatment costs were generally higher for patients switching to vedolizumab. The exception was in patients with ulcerative colitis who switched to golimumab. Regarding outcomes, adalimumab and other switchers had Our treatment choices when switching biologics in IBD patients should primarily be guided by each unique clinical scenario. This is particularly pertinent when there is not always a benefit in outcomes from using newer therapiesThe cohort studied was derived from claims data and disease severity was determined by proxy variables. In addition, there are other factors contributing to the costs including point of care costs, and unique contracts between health care systems and payers which cannot be evaluated in this study design.However, this study is one more reminder to be cognizant of economic implications versus desirable outcomes when switching biologic therapy.


Cyto-histopathological correlation is a key player in measuring quality in a quality programme . It was The Special Issue collected together articles dealing with various aspects of cyto-histological correlation and its role in cytological diagnosis routine. Gynecological samples form the highest proportion of all cytological specimens. Its cyto-histological correlation as a part of quality assurance programmes was covered in the literature ,2. AsatuThyroid fine needle aspiration cytology is important and expanding field of cytology. Preoperative diagnosis of rare medullary carcinoma is essential for lesion management, so Asia-Pacific international multi-institutional cytomorphological analysis of smears prepared with different staining methods has impact on practice improvement and quality worldwide . A Prof.Pulmonary cytopathology is an emerging field with personalized medicine and immunotherapy related techniques application to cytology specimens in growing proportion. Swedish colleagues studied concordance of PD-L1 expression between cytology and histology specimens in pulmonary non-small cell carcinomas; the concordance was better in bronchoalveolar lavage and bronchial brushing than in pleural effusions . This kiThe contributory role of cell blocks (CBs) in salivary gland cytology classified according to The Milan System for reporting Salivary Gland Cytology (MSRSGC) was demonstrated by Tommola et al. . The appNew cytopathology terminologies were also studied in three other papers ,13,14. TThe International System for Reporting Serous Fluid Cytology (TIS) was applied by Portuguese and Greek cytopathologists ,14. A seLast, but not least I thank all authors, reviewers, editors and editorial office staff who contributed to the success of this Special Issue.


Studies have shown that health education can improve dietary intake, exercise, and energy balance, which improves health outcomes and quality of life. However, diverse low-income older adults may have low self-efficacy coupled with potentially negative opinions regarding the aging process. Emerging research suggests that asset-based approaches utilizing persuasive and hopeful messages may be particularly effective with diverse populations of older adults who may be struggling with negative perceptions of self-efficacy. Research also shows that health behavior change interventions are most likely to be successful among diverse populations when they incorporate messages of resilience and facilitate information sharing and diffusion among participants. This presentation outlines the program curriculum development process of a student-led health promotion program by an interdisciplinary team of university researchers. Public health, dietetics, and communication faculty utilized Persuasive Hope Theory (PHT) and Self-Efficacy Theory to create a 15-week program to improve fruit and vegetable intake and physical activity among low-income adults aged 55+ living in Anchorage, Alaska. We will also detail the curricular components for this NIA-funded program which will be delivered in Fall 2022.


Understanding who will experience cognitive dysfunction and dementia is as important as identifying methods to combat such deterioration. This symposium seeks to highlight new advances in understanding cognitive deterioration and promote resilience in adulthood. Odd and colleagues utilized a national sample  to show that 9-year decreases in executive function and episodic memory predicted increased risk of dying. Use of a brief cognitive assessment administered via telephone was unique – a method that may assist clinicians administering cognitive screenings to older adults in isolated areas. Graham and colleagues utilized a daily diary approach in 116 older adults (aged 60-90) to show that greater daily fluctuations in mindfulness were associated with higher episodic memory and executive functioning. Further, mediational evidence suggested that on days when mindfulness was greater, individuals perceived a younger subjective age. Willroth and colleagues provide evidence that higher scores on eudaimonic well-being in older adults (n=349) predicted greater cognitive resilience. Specifically, even though some participants had neuropathological burden , they did not exhibit pronounced cognitive declines. Using data from 14 longitudinal studies, Yoneda and colleagues examined the impact of physical activity on cognitive impairment and death. Multi-state survival analyses demonstrated engagement in more physical activity reduced risk of cognitive impairment and death. This symposium suggests that examining changes in cognition, incorporating subjective and objective indices of cognitive impairment, utilizing long-term longitudinal and daily diary designs, and testing key modifiable behaviors is crucial to understanding and promoting optimal cognitive functioning in adulthood.


Gordeeva et al. described a 3D embryoid body differentiation model and compared the spatiotemporal growth and patterning dynamics of embryoid bodies formed from different stem cell origins and culture conditions. Min et al. profiled the proteome and the protein phosphorylation of blastoids–blastocyst-like 3D structures derived from extended pluripotent stem cells (EPSC). By comparing the protein expression profiles of EPSC blastoids with mouse blastocysts, they indicated that glucose metabolism is key to blastoid formation and brought new insights into the similarities and differences between blastoid and blastocyst at the proteome level. In addition, Luijkx et al. provided a comprehensive comparison of current protocols for mouse (Human pluripotent stem cells (PSCs), including embryonic stem cells (ESCs) and induced pluripotent stem cells (iPSCs), have enabled the modeling of human development and helped to illuminate mechanisms of monogenic disease, complex disease, and cancer. Lately, the striking ability of PSCs to self-organize has engendered three-dimension (3D) models of human development. The 3D embryonic cell models partially reconstruct the complex architecture of mammalian early embryonic structures and therefore hold great potential for stem cell and developmental studies. In this Research Topic, or mouse  and humaor mouse  blastoidex vivo organoid cultures has gained substantial attention as a model to study regenerative medicine and diseases in several tissues since the seminal work in 2009 . A clear example is the development of stem cell derived kidney progenitors and organoids that may be utilized to provide a reliable source of proximal tubule cells that are needed in commercializing the bioartificial kidney device. Liu et al. reviewed kidney disease model studies using in vitro tools including kidney organoids derived from normal human fetal/adult tissues, human PSCs and primary tissues of kidney cancer. They covered many topics including polycystic kidney disease and other genetic kidney diseases, and non-genetic kidney diseases. Both papers also discussed the remaining challenges of translating advances in kidney organoid research into new therapies.Chronic kidney disease (CKD) is a general term for heterogeneous disorders affecting kidney structure and function. When kidney function continues to decline, CKD patients may develop end-stage renal disease . Organ transplantation and dialysis continue to represent the only therapeutic options available. However, in the last two decades major advances in stem cell biology, gene editing, and bioengineering are now delivering options in regenerative medicine to treat CKD. Ramirez-Calderon et al. summarized the most advanced 3D methods for deriving human cardiac organoids from human PSCs and discussed the potential applications of cardiac organoids in the pharmaceutical and bioengineering fields, including the emerging question of Severe Acute Respiratory Syndrome CoronaVirus 2 (SARS-CoV-2) infection in the heart.Human cardiac lineages can be differentiated in traditional two-dimensional monolayer culture or by adopting 3D culture methods. Klein et al. argue that paying due attention to culture environments is critical to improve the reproducibility and translation of preclinical research. They outline the main sources of cell culture environmental instability and deliver best practice recommendations, thus making an important step towards enhancing the physiological relevance of in vitro cellular models. Additionally, a higher resolution understanding of the molecular events unfolding during development or tissue homeostasis could guide better 3D differentiation protocols. Single-cell OMICs analysis promise to deliver unprecedented insights into human development and disease pathogenesis. In this Research Topic, Xu et al. applied single-nucleus RNA sequencing (snRNA-seq), which could resolve multiple cell types better than single-cell RNA sequencing (scRNA-seq), to profile cell types, dynamics of cellular composition, and hepatocyte differentiation trajectories during postnatal murine liver development. A complete understanding of the development of complex organs such as the brain requires not only cell type taxonomy (which scRNA-seq excels at) but also spatial information of cells or genes at the organ level. Cheng et al. applied Stereo-seq, a DNA nanoball patterned array-based high-resolution spatial transcriptomic technology, to medial structures in postnatal mouse brain. Their data provided subcellular distribution of 27,330 genes, region-specific gene regulatory networks, 41 cell types localized in different regions. This rich resource for developmental study is accessible as an open and interactive database (https://db.cngb.org/stomics/datasets/STDS0000139?tab=explore). Li et al. performed integrative scRNA-seq and single cell assay for transposase-accessible chromatin sequencing (scATAC-seq) analysis in mesenchymal stem/stromal cells derived from placenta (PMSCs). Their data revealed subsets of PMSCs and nominated potential cis and trans regulatory factors in the subtypes.These primary research and reviews highlight the fact that organoids are heterogeneous in shape and size; moreover, the absence of blood supply and interactions with non-parenchymal cell types limit their potential. For these reasons, future works are needed to standardize organoid cultures, including co-cultures with other cells , and to improve cell maturation to generate more faithful models. To this end, improvements in culture methodology could make 3D stem cell models more robust and reproducible. Shams et al. showed that signaling through the chemokine receptor CXCR4 is essential to normal early activation, proliferation and self-renewal of muscle stem cells (or satellite cells), which are responsible for regenerating muscle fibers following acute skeletal muscle injury. Among mammals, deer has the unique ability to fully regenerate a lost organ, the antler. Guo et al. explored the gene expression changes during the activation of the pedicle periosteum (harboring stem-like cells) that triggers the initiation of antler regeneration. Their findings suggest that calreticulin (CALR), an androgen response gene, is likely a downstream mediator of androgen hormones for initiating antler regeneration.Besides high-through profiling of mRNA and chromatin accessibility, mechanistic dissection of regulatory pathways during tissue regeneration pays dividends for improving stem cell differentiation and developing novel therapies. In this regard, The topic editors hope the readers enjoy reading these new papers centered around stem cell models as much as we do. The exciting research advances summarized in this volume will undoubtedly have a positive impact on the translational values of stem cell models.


Community gerontology integrates scholarship on aging and communities through the lens of mesolevel environments, the diverse continua of settings linking micro and macro contexts of aging. This interdisciplinary symposium brings together research exploring the interconnections of older adults’ engagement across and within the socio-ecological levels of their lived experiences, place-based communities, and policy contexts. Yeh et al.’s paper elucidates the promises of visual methods in critical qualitative research with older adults to subvert power dynamics and advance social justice in gerontology. Latham-Mintus’ paper explores how “weak ties” created by the interaction of social infrastructure within geospatial places and spaces can facilitate longer, healthier lives. Reyes’ paper uses an intersectional life course perspective to explore placemaking as civic participation among Latinx immigrants and African American older adults across time and social environments. Plasencia’s paper focuses on aging in community among diverse older adults using a photovoice to assess their perceptions and needs within the lived urban environment. Pope and colleagues explore how a multi-state sample of older adults perceive their roles in age-friendly initiatives at individual, organizational, and community levels. Taken together, the papers discuss and contextualize the multidirectional ways older adults engage their place-based communities within larger macro sociopolitical structures – an analysis that highlights the embeddedness of mesolevel community environments both within and between micro and macro spheres. This session further speaks to the importance of centering older adults’ experiences in community gerontology by illuminating the ways older adults not only age in community but through layers of community.


Recent years have seen important progress in the characterisation and refinement of organoid culture systems. Here, we address several open questions in the field, including how closely organoids recapitulate the tissue of origin, how well organoids recapitulate patient cohorts, and how well organoids capture diversity within a patient. We advocate deeper characterisation of models using single cell technologies, generation of more diverse organoid biobanks and further standardisation of culture media.Organoids have become a prominent model system in pulmonary research. The ability to establish organoid cultures directly from patient tissue has expanded the repertoire of physiologically relevant preclinical model systems. In addition to their derivation from adult lung stem/progenitor cells, lung organoids can be derived from fetal tissue or induced pluripotent stem cells to fill a critical gap in modelling pulmonary development  Customised media have been developed to expand specific cellular subpopulations from iPSCs; in the airways, basal cells and secretory progenitor cells have all been induced from iPSCs  and, whein vivo tissue of origin remarkably well, despite the absence of stroma in vitro  of single nucleotide variants (SNVs) and copy number alterations (CNAs). Although whole exome sequencing has been performed in some studies , others The extent to which lung cancer organoids diverge from tumour tissues at the phenotypic level is much less clear. Since organoid culture systems were originally developed to expand epithelial stem cells , it is uThe majority of lung organoid cultures are currently performed as mono  cultures, although investigations of epithelial-fibroblast  or epithin vivo complexity of epithelial-stromal or epithelial-immune interactions, nor systemic variables such as nutrient availability, mechanical forces and circadian rhythms.While we advocate a better phenotypic characterisation of lung organoids to investigate their resemblance to lung tissue, it must be emphasised that organoids will always remain a reductionist model. The generalisation or translational relevance of results obtained in this culture system is best validated using orthogonal model systems  or datasets (including publicly available omics datasets). Moreover, it is not possible to reproduce the complete A second important aspect of organoid modelling is the extent to which it is possible to capture the biology of the target population. Primary human bronchial epithelial cell cultures can show wide inter-patient variability in differentiation potential and response to stimulation, and so studying sufficient numbers of patient cultures is crucial, particularly when studying phenomena that are likely to vary with biological characteristics of the donor, such as age and/or sex . At presOrganoids have been derived from patients across a wide range of respiratory diseases, including pulmonary fibrosis , primaryTo date, lung cancer research has benefited most from organoid-based disease modelling. As many hundreds of organoid lines have been developed by multiple laboratories worldwide, it is possible to assess the extent to which they reflect non-small cell lung cancer (NSCLC) patient cohorts. Surprisingly, organoid establishment rates are similar for lung squamous cell carcinomas or adenocarcinomas , despiteTo date, most studies have generated lung cancer organoids from surgical resections of primary tumours. To our knowledge, no organoid models have been generated from pre-invasive disease, but pre-cancer organoids would be particularly valuable to study events in early tumourigenesis. Since most lung cancer patients die from metastatic disease, representing these in organoid collections would be valuable. One study established organoids from malignant effusions from patients with advanced lung cancer with a high success rate , suggestAn alternative approach to deriving organoids from lung disease patient cohorts, is to use the available model systems to investigate specific hypotheses related to the disease process. In this regard, pluripotent cell-derived organoids have proved useful pulmonary fibrosis models. Introducing Hermansky-Pudlak syndrome (HPS) mutations associated with interstitial pneumonia using CRISPR-Cas9 promotes fibrotic changes in ES-derived lung organoids  or iPSCsIntra-patient heterogeneity likely represents an understudied source of variation in lung organoid research. At present, authors typically report the diagnosis of the patient from whom organoids were derived and the tissue of origin. However, airway epithelial cell phenotype is known to vary in the proximal-distal axis within normal lungs with cells from the upper airways having distinct transcriptomic profiles , innate in vitro. Indeed, one study reported a low correlation of variant allele frequencies (VAFs) between organoids and original tumours in approximately half of the samples analysed (Lung cancers are genetically and phenotypically heterogeneous, but the extent to which this is maintained in lung cancer organoid cultures is so far poorly characterised. Given the variable establishment rates of lung cancer organoids, bottlenecks are expected that restrict heterogeneity analysed . Evidencanalysed  and coloanalysed . This coanalysed , there ianalysed . The estanalysed . Evaluatin vivo processes, the ability of organoid collections to accurately reflect population level inter-individual variability and intra-patient heterogeneity (Lung organoids provide a cell culture platform to study lung development, stem/progenitor cell biology and disease pathogenesis. Several open questions remain, however, concerning their ability to recapitulate the tissue of origin and ogeneity . We advo


Oncogenic viruses, including hepatitis B virus (HBV), hepatitis C virus (HCV), human papillomavirus (HPV), Epstein Barr virus (EBV), and Kaposi Sarcoma Herpes virus (KSHV) contribute to a significant proportion of the world’s cancers. Given the sizeable burden of virus mediated cancers, development of strategies to prevent and/or treat these cancers is critical. While large population studies suggest that treatment with hydroxymethylglutaryl-CoA reductase inhibitors, commonly known as statins, may reduce the risk of many cancer types including HBV/HCV related hepatocellular carcinoma, few studies have specifically evaluated the impact of statin use in populations at risk for other types of virus mediated cancers.Studies of populations with HBV and HCV suggest a protective, dose-dependent effect of statins on hepatocellular carcinoma risk and support the theory that statins may offer clinical benefit if used as chemoprophylactic agents to reduce liver cancer incidence. However, no population level data exists describing the impact of statins on populations with other oncogenic viral infections, such as HPV, EBV, and KSHV.Further study of statin use in diverse, global populations with or at high risk for oncogenic viral infections is essential to determine the impact of statin therapy on virus mediated cancer risk. Cancers caused by infections represented more than 13% of the global cancer burden in 2018, including more than 1.2 million cancers caused by viruses  for lipophilic statin users and 0.51 [0.31–0.85] for hydrophilic statin users) . In contIn contrast to HBV/HCV, few epidemiologic studies describe the impact of statin use on HPV-, EBV-, or KSHV-mediated cancers. For HPV, one retrospective cancer database study of 1638 individuals with head and neck cancers found a statistically significant inverse association between ever using a statin and death from HPV + head and neck cancers  .Available data suggest a protective, dose-dependent effect of statins on HCC risk in populations with chronic HBV and/or HCV infections. Thus, statins may show clinical benefit if used as chemoprophylactic agents to reduce the public health burden of HCC, and randomized clinical trials evaluating the effectiveness of statins in HCC outcomes both with other therapies (NCT03275376) and to prevent recurrent HCC (NCT03024684) are ongoing. Trials being planned should include comparisons of lipophilic or hydrophilic statins in their designs.The promise of statins in preventing HCC warrants extrapolation of epidemiologic and clinical study of statin therapy to populations at risk for other oncogenic viral infections, particularly HPV, EBV, and KSHV. Importantly, despite the much larger global burden of cervical cancer, the only published study describing the impact of statins on HPV is in HPV-related head and neck cancers, which are predominantly diagnosed in men in high income countries. Future studies must rectify this disparity by evaluating the impact of statins on cervical cancer, particularly in low- and middle-income countries where cervical cancer rates are higher due to poor access to HPV vaccines and surveillance programs, but also in high income countries where cervical cancer remains an important cause of cancer morbidity and mortality despite robust HPV prevention programs. Statin therapy might prevent or slow the development of cervical cancer if initiated immediately after detection of high-risk HPV subtypes or cervical dysplasia in women undergoing cervical cancer screening. Though pre-clinical data suggest that statin therapy may ameliorate EBV-related cancers, no epidemiologic studies have evaluated statins in prevention or as an adjunctive therapy in at risk populations. Such studies are needed to determine whether statin intervention trials are warranted to prevent EBV-related cancers. Though KSHV afflicts a large proportion of the population, particularly in sub-Saharan Africa, no investigations into the ability of statin therapy to limit the development of KSHV-associated cancers exist; study of the relationship between KSHV and statins should be initiated via in vitro and animal model studies. Finally, HIV hugely impacts risk of morbidity and mortality in those co-infected with the oncogenic viruses covered in this Review, and several anti-retroviral therapies in widespread use are known to contribute to dyslipidemia. Future research should include investigation of statins as agents to prevent virus mediated cancers in people with HIV, as these individuals may have different outcomes or require different statin doses.The studies outlined in this article provide preliminary evidence that statins may induce mechanisms that slow virus-mediated cancer development, which should be further investigated in epidemiologic studies of populations at risk for HPV, EBV, and KSHV infection. Randomized trials and large community-based prevention trials prospectively evaluating use of specific statins in populations with or at high risk for oncogenic viral infections will be needed to further explore the potential benefit of statins in decreasing virus mediated cancer risk.


Co-occurrence of obsessive-compulsive disorder (OCD) and autism spectrum disorder (ASD) features is well stablished. Diagnosis of OCD increases the risk of a later diagnosis of ASD, and vice versa. Moreover, a recent combined genome-wide association study identified a shared polygenic risk between the two disorders. Our preliminary results also indicate that OCD patients have higher levels of autistic traits than individuals from the community.To determine which autistic dimensions  are predictors of OC symptoms.39 OCD patients  answered the Portuguese versions of the Autism-Spectrum Quotient for Adults and Obsessive Compulsive Inventory – Revised (OCI-R). Spearman correlation and linear multiple regression tests were performed using SPSS.The OCI-R global score showed positive correlations with some AQ dimensions . The regression model showed that attention to detail  and attention switching  explained 36% of obsessive-compulsive symptoms variance.Our results are in line with a dimensional perspective of psychopathological continua and indicate that the overlap between OCD and ASD occurs through shared neurocognitive processes. We suggest that, besides being a predisposing factor for social difficulties  in ASD, attention to detail and deficits in attention switching may also lead to difficulties to dismiss repetitive thoughts or extinguish behaviours in OCD. Future studies should investigate the distinctive features and underlying processes between OCD/ASD.


Although minimally invasive percutaneous disc nucleoplasty (PDN) has been widely used for discogenic back pain or soft-disc herniation of the lumbar spine, complications can occur. Although rare, iatrogenic vascular injuries during PDN are serious complications that can be fatal without rapid diagnosis and effective management. Here, we present the case of a 38-year-old male patient with an injury to the right fifth lumbar artery that occurred during PDN, which was successfully treated using emergent transarterial embolization. To the best of our knowledge, this is the first report of successful transarterial embolization without open hematoma evacuation for a lumbar artery injury that occurred during PDN.


Regulatory T cells (Treg) are a major immunosuppressive cell subset in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies, whereupon Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these compensatory mechanisms may be patients with locally advanced PCa undergoing neoadjuvant therapy (neoTx). In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.+ myofibroblastic cancer-associated fibroblasts (myCAF) and increased proportions of CD8+ cytotoxic T lymphocytes in the tumor. In order to understand these dynamics and to uncover stage-specific actional strategies involving Tregs, pre-clinical models that allow the administration of neoTx to different stages of PCa may be a very useful platform.Regulatory T cells (Treg) are one of the major immunosuppressive cell subsets in the pancreatic tumor microenvironment. Tregs influence tumor growth by acting either directly on cancer cells or via the inhibition of effector immune cells. Treg cells mechanisms form a partially redundant network with other immunosuppressive cells such as myeloid-derived suppressor cells (MDSC) that confer robustness to tumor immunosuppression and resistance to immunotherapy. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas an inverse association was seen in advanced PCa, urge a comprehensive analysis of the immunosuppressive profile of PCa throughout tumorigenesis. One relevant context to analyse these complex compensatory mechanisms may be the tumors of patients who underwent neoTx. Here, we observed a parallel decrease in the numbers of both intratumoral Tregs and MDSC after neoTx even in locally advanced PCa. NeoTx also led to decreased amounts of αSMA PCa is one of the deadliest human neoplasms and is projected to become the second leading cause of cancer-related death worldwide by 2030 . Its poo+CD25+Foxp3+ T cells, are a subpopulation of lymphocytes that are crucial in maintaining tolerance to self-antigens and innocuous foreign antigens under physiological conditions, but can also be co-opted by tumor cells to avoid the host immune response . TAM. TAM+ mypatients .Even in locally advanced tumors, perioperative chemotherapy led to a parallel decrease in both Treg and MDSC which was associated with tumor shrinkage and prolonged survival. The results obtained in preclinical studies where after Treg depletion, MDSCs concomitantly decreased in early tumors whereas the inverse association was seen in advanced PCa, urge a comprehensive analysis of the phenotype and frequency of these major immunosuppressive cell subsets through pancreatic tumorigenesis. Such a “human” example demonstrates that the reaction of Treg cells and MDSC in locally advanced PCa may not actually be antagonistic but concurrent, and that these two immune cell populations should not be perceived as being mutually suppressive or substituting. The question whether the compensatory network between Treg cells and MDSCs intensifies in patients with late-stage metastatic PCa, remains yet unexplored.Therefore, the underlying mechanisms behind the complex interplay between myeloid cells and Treg cells still needs further elucidation . A bette


Our results imply that microorganisms classically considered as sulfate reducers control the potential for DNRA within coastal sediments when redox conditions oscillate and therefore retain ammonium that would otherwise be removed by denitrification, exacerbating eutrophication.The oscillating redox conditions that characterize coastal sandy sediments foster microbial communities capable of respiring oxygen and nitrate simultaneously, thereby increasing the potential for organic matter remineralization, nitrogen (N)-loss and emissions of the greenhouse gas nitrous oxide. It is unknown to what extent these conditions also lead to overlaps between dissimilatory nitrate and sulfate respiration. Here, we show that sulfate and nitrate respiration co-occur in the surface sediments of an intertidal sand flat. Furthermore, we found strong correlations between dissimilatory nitrite reduction to ammonium (DNRA) and sulfate reduction rates. Until now, the nitrogen and sulfur cycles were assumed to be mainly linked in marine sediments by the activity of nitrate-reducing sulfide oxidisers. However, transcriptomic analyses revealed that the functional marker gene for DNRA (nrfA) was more associated with microorganisms known to reduce sulfate rather than oxidise sulfide. Our results suggest that when nitrate is supplied to the sediment community upon tidal inundation, part of the sulfate reducing community may switch respiratory strategy to DNRA. Therefore increases in sulfate reduction rate in-situ may result in enhanced DNRA and reduced denitrification rates. Intriguingly, the shift from denitrification to DNRA did not influence the amount of N The permeable sandy sediments that fringe coastlines act as highly effective biocatalytic filters that remineralize organic carbon, and remove fixed nitrogen through denitrification –5. The mMany of the microorganisms within permeable sediments appear to be adapted to the oscillating oxic and anoxic conditions . Such adTypically, microorganisms in marine sediments employ different electron acceptors over depth, largely in accordance with their decreasing energy yield, which often leads to an apparent spatial separation of sulfate reduction from nitrate reduction –24. ThisSeveral lines of evidence suggest that sulfate reduction in intertidal permeable sediments should be tolerant of nitrate. Sulfate reducers are present and highly active in the upper layers of sediment, even though this area is frequently exposed to both nitrate and oxygen , 37–40. Desulfovibrio vulgaris can prevent this competitive inhibition of sulphite reductase via constitutive expression of periplasmic cytochrome c nitrite reductase (Nrf) to remove the nitrite, although there are contrasting reports as to whether this is also linked to energy generation http://enSupplementary InformationSupplementary Tables 4, 5


Cancer therapies for older adults have accelerated at breakneck speed in the last few decades, necessitating evaluation of their delivery and uptake to ensure patients receive their maximum benefit. Among the vast array of evaluation tools available, those utilizing naturally occurring data—data produced without intervention from a researcher—are a powerful but underused tool. In this presentation, we will review two methods for examining naturally occurring data, participant observation and conversation analysis (CA), in an educational intervention study of multiple myeloma patients receiving autologous stem cell transplant. First, we will review how participant observation of nurse-led education visits (n=70) was incorporated to iteratively improve video-based education. Next, we will review use of CA in reviewing audio recordings containing reference to the education videos of 12 nurse-led education visits (1011 minutes of audio). Ultimately, understanding the purposes of and ways of using naturally occurring data have potential for improving the evaluation of patient education.


For this qualitative, pilot study, seven Massachusetts nursing home Directors of Nursing (DONs) were interviewed remotely about palliative care provision before and during the COVID-19 pandemic. Interview data were analyzed using thematic analysis. Palliative care addresses physical, emotional, psychological, and spiritual suffering that accompanies serious illness. Symptom management and goals of care is especially valuable for seriously ill nursing home residents. We investigated the solutions nursing home staff developed to provide palliative care during the COVID-19 pandemic despite restrictions on external resources. Before the pandemic, palliative care was delivered primarily by nursing home staff depending on formal and informal consultations from palliative care specialists affiliated with hospice providers. When COVID-19 lockdowns precluded these consultations, nursing staff did their best to provide palliative care, but were often overwhelmed by shortfalls in resources, resident decline brought on by isolation and COVID-19 itself, and a sense that their expertise was lacking. Advance care planning conversations focused on hospitalization status and options for care given COVID-19 resource constraints. Nevertheless, nursing staff discovered previously untapped capacity to provide palliative care on-site as part of standard care, building trust of residents and families. Nursing staff rose to the palliative care challenge during the COVID-19 pandemic, albeit with great effort nursing home payment and quality standards should support development of in-house staff capacity to deliver palliative care while expanding access to the formal consultations and family involvement that were restricted by the pandemic.


The population of family caregivers (FCGs) of persons with Alzheimer's Disease and related Dementias (ADRD) is growing, as is the proportion of males taking on this traditionally female role. Most caregiving research has mainly focused on females. Although female caregivers have reported more negative outcomes, men still report significant levels of burden. With the aging population and increased need for caregivers, there is a gap in knowledge exploring the male caregiving experience. Understanding male caregiving experiences can inform clinicians on developing future strategies to tailor support for this underrepresented group. The purpose of this qualitative descriptive study was to explore the experiences of male FCGs of people with ADRD. The Caregiver Identity Theory (CIT) was used to guide the study exploring participants’ perception of self-identity within their caregiving relationship and self-identity as a male. Eleven male caregivers, recruited through social media and community resources, were interviewed by telephone or Zoom. Interviews were recorded, transcribed, and analyzed using thematic analysis. Four major themes emerged highlighting males’ struggles with the unfamiliar caregiving role and changing identity; their acknowledgement of personal growth and discovery through caregiving, challenges in finding the “right” kind of support, and perceived reshaping of masculinity through the caregiving role. Male caregivers express unique experiences as FCGs suggesting future research is needed to explain gender differences in caregiving and identify additional factors that influence male caregivers’ experiences. Furthermore, findings indicate clinicians should tailor support strategies for male FCGs’ as they fulfill this potentially unfamiliar role.


Molecular psychiatry research needs a deeper characterization of emotional and cognitive neural underpinnings, along with a broader recognition of trauma-related circuitries and their involvement in shared pathological endophenotypes. One such endophenotype is unbalanced approach avoidance conflict (AAC), a highly recurrent trait of psychopathology. A translationally validated rodent model of AAC is the elevated plus maze (EPM) test, recently shown to be pharmacologically controlled in human and rodents via homologous neural substrates. Thanks to this test, we identified the involvement of the epigenetic enzyme LSD1 as a molecular restrainer of anxiety. We identified LSD1 aberrant regulation within the hippocampus of suicidal victims, suggesting its broad functional involvement in maladaptive behaviors. Interestingly, thanks to the parallel employment of rodent models, we evaluated a stress-related LSD1 homeostatic regulation that transiently limits memory formation-instrumental gene expression in the hippocampus upon trauma. Our work shed new light on epigenetic processes devoted to trauma resiliency through a negative regulation of anxiety plasticity.No significant relationships.


This quantitative cross-sectional sub project investigated the effects of organizational context and individual characteristics on psychological empowerment of care aides working in nursing homes. We analyzed data collected from 3765 care aides from 91 nursing homes across Western Canada between 09/2019 and 03/2020. From the random-intercept mixed effects regression models we identified significant predictors at different levels for each component of psychological empowerment. At the organizational outer context level: region and home ownership model. At the inner context (care unit) level: formal interactions , evaluation , culture , communication , and social capital . At the individual level: care aides’ sex, language and job satisfaction.These findings suggest important ways in which contextual elements may influence staff quality of work life characteristics and underscore the need to consider context operating at different levels, as well as consider individual and contextual interaction.


Area-level residential instability (ARI), an index of social fragmentation, has been shown to explain the association between urbanicity and psychosis. Urban upbringing has been shown to be associated with decreased gray matter volumes (GMV)s of brain regions corresponding to the right caudal middle frontal gyrus (CMFG) and rostral anterior cingulate cortex (rACC).We hypothesize that greater ARI will be associated with reduced right posterior CMFG and rACC GMVs.Data were collected at baseline as part of the North American Prodrome Longitudinal Study. Counties where participants resided during childhood were geographically coded using the US Censuses to area-level factors. ARI was defined as the percentage of residents living in a different house five years ago. Generalized linear mixed models tested associations between ARI and GMVs.This study included 29 HC and 64 CHR-P individuals who were aged 12 to 24 years, had remained in their baseline residential area, and had magnetic resonance imaging scans. ARI was associated with reduced right CMFG  and right rACC volumes . The interaction terms (ARI X diagnostic group) in the prediction of both brain regions were not significant, indicating that the relationships between ARI and regional brain volumes held for both CHR-P and HCs.Like urban upbringing, ARI may be an important social environmental characteristic that adversely impacts brain regions related to schizophrenia.No significant relationships.


Ancestral sequence reconstruction (ASR) infers predicted ancestral states for sites within sequences and can constrain the functions and properties of ancestors of extant protein families. Here, we compare the likely sequences of inferred nitrogenase ancestors to extant nitrogenase sequence diversity. We show that the most-likely combinations of ancestral states for key substrate channel residues are not represented in extant sequence space, and rarely found within a more broadly defined physiochemical space—supporting that the earliest ancestors of extant nitrogenases likely had alternative substrate channel composition. These differences may indicate differing environmental selection pressures acting on nitrogenase substrate specificity in ancient environments. These results highlight ASR's potential as an in silico tool for developing hypotheses about ancestral enzyme functions, as well as improving hypothesis testing through more targeted in vitro and in vivo experiments. Ancestral sequence reconstruction (ASR) is widely used for modeling sequence properties and functions of ancient enzyme variants. Maximum-likelihood reconstructions combine substitution models with aligned sequence data and phylogenetic information to calculate the residue likelihood of aligned sites for all internal nodes in a tree . This apNitrogen-fixing nitrogenases are the lynchpin of Earth's biological nitrogen cycle, and have been extensively studied for their role in global biogeochemistry . Modern 2) fixation, modern nitrogenases can promiscuously reduce other linear, triple-bond-containing molecules at the FeMoCo active site (2), carbon monoxide (CO), acetylene (C2H2), and hydrogen cyanide . A library of plausible sequence ancestors for this collection of sites was generated, and their relative probabilities calculated. We applied a simple hypothesis-testing strategy: Are likely ancestral active site sequence states found within sampled extant nitrogenase diversity? We find that this is not always the case, permitting the possibility that early nitrogenase ancestors had substrate binding channels with properties distinct from modern enzymes.A higher affinity for alternative substrates in ancestral nitrogenases would likely require different amino acid residues in the substrate-binding part of the enzyme (the substrate channel), while preserving catalytic activity. As ASRs are inherently probabilistic, individual sites may be inferred to have several possible ancestral states with non-negligible probabilities. Variation across sampled extant diversity allows the combinations within likely ancestor sequences to explode, producing a far greater number of plausible sequence ancestors than can be experimentally tested. Here, we use ASR to reconstruct the amino acid identities of alignment sites directly interacting with the substrate binding channel in the common ancestor of the active site-containing nitrogenase subunit (Azotobacter vinelandii Nif (P > 0.10) in the predicted nitrogenase ancestor  and Group II Nif  of reconstructed ancestors contained substitutions yielding a combination not represented by extant sequences or physicochemical types . Of the The effects of substitution models and topology on predicted ancestor sequence and type were also evaluated by repeating tree construction and ASR under WAG + R10 (the highest likelihood non-LG model) and BLOSUM62 + R10 . Substitution models slightly impacted recovered tree topologies within recently diverged lineages but did not alter phylogenetic relationships between major nitrogenase types and their outgroups. Relative likelihoods for specific amino acids are generally conserved at sites 495, 496, and 603, and sample the same plurality at site 576  and site 348  . MoreoveChloroflexales bacterium ZM16-3. The top ten most-likely ASR residue combination physicochemical types were represented by very few extant sequences, and only within the divergent group of Nif that also contains the alternative nitrogenases. Divergent homologs within this clade may sample ancestral sequence patterns to a greater extent than type I or II nitrogenases. If so, characterizing these extant genes could provide useful analogs for ancestral phenotypes.These results suggest that the inferred ancestor of Nif, Vnf, and Anf nitrogenases most likely contained a substrate channel sequence distinct from that found in extant sequence space. Twenty-two of the 23 highest likelihood sequence combinations of the five variant substrate channel ancestral sites are not observed within known modern nitrogenases; the only represented sequence pattern occurs in only one observed extant enzyme, that of The conservative substitutions observed in the highest likelihood predicted ancestors are unlikely to radically influence substrate affinity or binding, at least when compared with the extant enzymes in the Nif/Anf/Vnf group. In the case of HCN, for example, because both modern Vnf  and Nif Extant nitrogenases that remain unsampled and excluded from the tree could contain currently missing high-likelihood sequence combinations in the ASR. Additionally, likelihood ratios calculated from only a handful of sites do not represent overall sequence likelihoods, as site likelihoods are calculated independently. Thus, the most-likely ancestral site combinations in the substrate channel are unlikely to identify the sequence in the most-likely overall ancestor. However, the likelihood calculations for these substrate binding sites may be more informative for inferring ancestral phenotype changes than the overall ancestral sequence of the enzyme. Indeed, physicochemical type combinations predicted by the ASR are more robust to changes in substitution model and tree topology than sequence-level variation ; this unThe results highlight the value of ASR as a first step in evaluating enzyme evolution hypotheses. In some cases, ASR itself may prove sufficient to refute certain evolutionary hypotheses; for example predicted ancestral states may be sterically incompatible with hypothesized substrate interactions or protein folding. Such results would preclude additional experimental work. It is also possible that when ASR fails to identify combinations of key ancestral residues absent from extant diversity, the null hypothesis of uniform phenotype across the reconstructed history should be preferred. However, even in this case, ASR will efficiently identify key sites to target for mutagenesis for in vitro or in vivo analyses—such as the novel sequence and type combinations sampled in this work.A. vinelandii (WP_012698832.1). Hits were included for molybdenum (NifD), vanadium (VnfD), and iron-only (AnfD) nitrogenases and manually curated to remove partial sequences, prune oversampled clades, and ensure the presence of conserved sequence features known to be critical for N2 reduction . The curated initial data set included 385 nitrogenase sequences and 385 outgroup sequences from light-independent protochlorophyllide oxidoreductases (nfaD; nif/anf/vnf ancestor as an internal node in the tree. The tree was rooted along the split between nitrogenases and the other oxidoreductases. Maximum-likelihood tree construction and subsequent ASR were performed in IQ-Tree (An initial data set of extant nitrogenase D-subunit homologs was constructed from hits gathered using BLASTp to search NCBI's non-redundant protein database with a query sequence from ductases . These iductases . Outgroues nfaD;  was prof IQ-Tree , under t


Transitions of care also exist within the operating room and contribute to an increased risk of adverse events.Hospitalized patients with severe infections may warrant intravenous (IV) antibiotics and surgical intervention for effective treatment of their infection. Surgical interventions require multiple transitions of care, which are well-studied sources of medication-related errors and inappropriate antimicrobial use. Furthermore, intraoperative bacteremia is common during elective surgeries. For patients requiring surgery for infection source control, maintaining adequate serum antibiotic levels may be particularly important in preventing bacteremia while infected tissue is surgically manipulated.Errors in antibiotic use in the perioperative period may negatively affect patient outcomes. Patients who experience diminished serum and tissue concentrations of antibiotics during surgical closure have higher risks of postoperative wound infections. no studies have investigated perioperative antibiotic use for inpatients already on IV antibiotic regimens. The lack of guidelines introduces further complexity because it allows for additional and potentially inappropriate antibiotic administration for patients already receiving broad-spectrum antibiotics. In this study, we examined the incidence and nature of inappropriate antibiotic use in the perioperative period among inpatients on IV antibiotic regimens.Although data exist on optimal timing of antibiotic administration for surgical antimicrobial prophylaxis,We conducted a retrospective cross-sectional study at a Veterans’ Affairs medical center. We included all inpatients who underwent noncardiac surgery in 2019 who were aged >18 years or older and were on an IV antibacterial regimen prior to surgery. Patients receiving only surgical antimicrobial prophylaxis were excluded. Study and waiver of consent were approved by the Institutional Review Board of the VA Ann Arbor Healthcare System.Through manual chart review by 2 physicians, we collected information on prescribed IV antibiotic regimens and timing of antibiotic doses in the perioperative period. Errors were classified as follows: missed doses, delayed doses, additional doses of prescribed IV antibiotics, or additional surgical antimicrobial prophylaxis. Delayed antibiotics were administered between 2 and 4 hours after the scheduled administration time, and missed antibiotics were either omitted or administered at least 4 hours after the scheduled administration time. Administration of surgical antimicrobial prophylaxis was defined as an error in patients already receiving IV antibiotics with the same or broader antimicrobial coverage.Of the 290 inpatients who underwent surgery in 2019, 163 patients (56%) received an IV antibiotic regimen prior to surgery. Complete data were available for 153 patients (94%). Errors in antibiotic administration in the perioperative period were identified in 60 patients (39%). The most common error was a missed dose of an IV antibiotic, which occurred in 22 patients (39% of errors)  was a missed dose of an antibiotic. Also, antibiotic overuse  accounted for 36% of errors. For example, patients already on broad-spectrum antibiotics for their infection were given additional antibiotics  for surgical site infection prophylaxis. We suspect that these errors are related to the multiple transitions of care in the perioperative period. Some errors are also likely related to documentation of medications administered during an anesthetic in a separate part of the electronic medical record than medications administered on the hospital ward.This study had several limitations. This was a single-center, retrospective study, and including multiple VA institutions would be a powerful next step. Second, the generalizability of these results may be limited because institutions using other electronic medical records may have different processes for documentation. However, we believe that the presurgical period in a patient’s hospitalization represents an underrecognized opportunity for antimicrobial stewardship given the transitions of care involved. and misuse of antibiotics is common in these patients. Education-based stewardship interventions and clinical decision support tools implemented in surgical units have been shown to lead to reductions in antimicrobial consumption and improved trends in percentages of resistant bacterial strains. However, research evaluating interventions that specifically target perioperative antibiotic misuse for inpatients already on antibiotics for active infections is limited. This period may present a valuable opportunity for multidisciplinary stewardship intervention. Collaboration between antimicrobial stewardship programs, anesthesiology, and surgery departments should be encouraged to improve local practices in perioperative antibiotic prescribing and to address systems-based challenges that lead to inappropriate antibiotic use. Further research will be essential to the evaluation of outcomes of patients who experience errors in perioperative antibiotic administration.In conclusion, surgical patients account for significant proportions of inpatient antibiotic use,


Socioemotional theories suggest that surviving challenging experiences enhances emotional resilience with age, yet the role of memories is overlooked in most models of emotion regulation. In parallel, cognitive accounts focus on age-related memory deficits associated with overlapping hippocampal neural representations across unique memories . We propose a novel framework supporting enhanced late-life reappraisal via hippocampal dedifferentiation of memory representations across current and past experiences. We review classic studies supporting mood benefits from integrated positive narratives following adverse autobiographical events. We also discuss multivariate neuroimaging evidence supporting overlapping hippocampal representations and ventromedial prefrontal cortex (vmPFC) involvement in meaning-making processes. We posit that greater hippocampal dedifferentiation across life memories may facilitate associative binding of current and past stressors as well as reappraisals in vmPFC. This process may provide avenues for generalizing past reappraisals to novel contexts and reducing cognitive demands of reappraisal. In addition, we discuss the possible age-related facilitation of this process, as a greater number of life experiences may become increasingly integrated with one another over the lifespan. These integrated neural associations may serve to make reappraisals from the past more readily accessible and applicable in new contexts over time, increasing routes to positive narratives following stress. We discuss future directions for testing components of the proposed model using multivariate neuroimaging methods. We conclude by briefly reviewing the possible clinical impact of mnemonic emotion regulation in promoting emotional well-being among older adults, using a strengths-based approach that leverages wisdom from experience and neural processes facilitated with age.


Despite growing research linking stressors with poorer cognition, less research explicitly considers stress from several sources, which often co-occurs and accumulate to influence health. We used the Global Gateway Harmonized data  to examine whether higher cumulative stress is associated with lower levels of and faster decline in cognitive function. We fit linear mixed effect models to assess the stress-cognition associations. After adjusting for all covariates, baseline cumulative stress was associated with lower baseline cognitive function in both HRS  and ELSA . Unexpectedly, higher baseline cumulative stress was associated with slower cognitive decline in HRS  but not in ELSA. The stress-cognition associations may differ among adults in the US and the UK. Future research should investigate how cumulative stress may operate differently to influence cognitive function across different populations.


Developmental theories suggest that midlife and older adulthood are stages in which individuals may begin to focus their time on contributing to society . During these stages, individuals may engage in socially responsible behaviors that protect against negative affect resulting from a lower sense of purpose in later life . Social responsibility includes both subjective measures of an individual’s felt contribution to society  and objective measures reporting actual time volunteering in different settings . We utilized data from the Midlife in the United States Refresher survey study and Biomarker Project  to explore how self-perceptions of generativity and time spent volunteering predicted negative affect for individuals in midlife and older adulthood. Preliminary analyses indicate that higher generativity (p<.001) and older age (p<.001), but not average time spent volunteering, were associated with higher negative affect. Further, we considered age as a potential moderator for the associations between generativity, volunteering, and negative affect. Age significantly interacted with generativity (p<.01), such that the effects of generativity on reducing negative affect decrease with age. Age did not significantly interact with time spent volunteering. Discussion will focus on how actual engagement in socially responsible behaviors and perceived societal contributions might yield different outcomes regarding protection against negative affect in mid- and later-life. Future directions may include exploring daily indicators of time spent volunteering, generative beliefs, and affect.


The purpose of this study is to determine whether a 12-week exercise course influences obese African American older women’s health capabilities and life satisfaction levels. Participants, who passed an initial screening and pre-assessment, were asked to measure current health capabilities and life satisfaction levels both prior to, and following, the 12-week exercise training. Researchers found that improvement in health capabilities, although there were no significant differences following exercise training participation, while obese African American older women had significantly higher life satisfaction levels. The findings suggest that a 12-week exercise training can be beneficial to enhance obese African American older women’s health capabilities and life satisfaction levels. Professionals in the field of gerontology and exercise should provide the appropriate exercise trainings so that obese African American older women would be able to optimize their life satisfaction levels.


Sarbecovirus), given that several closely related viruses have been discovered and sarbecovirus–host interactions have gained attention since SARS-CoV-2 emergence. We assessed sampling biases and modelled current distributions of bats based on climate and landscape relationships and project future scenarios for host hotspots. The most important predictors of species distributions were temperature seasonality and cave availability. We identified concentrated host hotspots in Myanmar and projected range contractions for most species by 2100. Our projections indicate hotspots will shift east in Southeast Asia in locations greater than 2°C hotter in a fossil-fuelled development future. Hotspot shifts have implications for conservation and public health, as loss of population connectivity can lead to local extinctions, and remaining hotspots may concentrate near human populations.Global changes in response to human encroachment into natural habitats and carbon emissions are driving the biodiversity extinction crisis and increasing disease emergence risk. Host distributions are one critical component to identify areas at risk of viral spillover, and bats act as reservoirs of diverse viruses. We developed a reproducible ecological niche modelling pipeline for bat hosts of SARS-like viruses (subgenus  Global Rhinolophus affinis , Rhinolophus marshalli (virus BANAL-236) and Rhinolophus pusillus (virus BANAL-103) ..SarbecovRhinolophus pearsonii . Most species' populations are currently declining (n = 8) or have unknown population trends . Local species loss values were almost twice the number of maximum gain . Along with climate change mitigation, strategies for maintaining landscape-level habitat connectivity will allow populations to reach refugia and lower extinction risk. This could be done by developing landscape connectivity surfaces that maximize diversity hotspot extensions, with monitoring effective dispersal through genetics [There are conservation implications from our findings. Range contractions are projected for several species, even for species using variable habitats, such as genetics ,86 and pgenetics .Our results identify broad regions where bats reported positive for sarbecoviruses most probably occur and co-occur. These hotspots coincide, but are not restricted only to Rhinolophidae diversity hotspots  and to hOur future projections assume models using present data perform adequately. However, our models do not account for biotic components that also interfere with suitability, so we are limited to inferences of distribution derived from landscape and climate drivers. Projections will therefore need validation with new data and new predictions. Related, small changes may be relevant for local health and conservation initiatives, and coronavirus hosts are a focus of increasing research . Data ch


Candida albicans, non-albicans strains including C. auris, Aspergillus and Fusarium isolates from worldwide sources.ARIA is a new annual global surveillance initiative collecting yeast and fungal isolates from worldwide designed to determine resistance to antifungal agents and trends over time. The ARIA program was developed in 2020 to provide a repository of recent clinical fungal isolates with known susceptibility profiles and to monitor resistance trends over time. ARIA reports the susceptibility patterns of its earliest data concerning echinocandins, second-generation triazoles, and fluconazole against clinical Isolates were collected from hospital worldwide during 2020, shipped to a central laboratory and re-identified by MALDI-TOF or molecular methods. MIC tests were performed by broth microdilution method in line with CLSI susceptibility testing standards. Percentage of susceptibility was calculated according to CLSI breakpoints. Antifungals tested were amphotericin B (AMB), anidulafungin (ANID), fluconazole (FLU), isavuconazole (ISA), micafungin (MIC), posaconazole (POS), and voriconazole (VOR). All testing was performed according to CLSI M27-A4 and M38-A2 methodologies.See table.Ongoing antifungal resistance surveillance like the ARIA program is of utmost importance in order to monitor the efficacy of traditional empirical therapy and for the development of novel antifungal agents. This repository and ongoing ARIA program will provide a resource to better support the biopharmaceutical industry’s goals to develop new and more potent antifungal agents.All Authors: No reported disclosures.