Housing Assistance Among Patients with Cancer: SEER-Medicare U.S. Department of Housing and Urban Development Data Linkage.

BACKGROUND: Lack of stable and affordable housing is an important social determinant of health. Federal housing assistance may buffer against housing vulnerabilities among low-income households, but research examining the association of housing assistance and cancer care has been limited. We introduce a new linkage of SEER-Medicare and Housing and Urban Development (HUD) administrative data. METHODS: Individuals enrolled in HUD public and assisted housing programs 2006-2021 were linked with cancer diagnoses 2006-2019 identified in the SEER-Medicare data from 16 states using Match*Pro probabilistic linkage software. HUD administrative data include timing and type of housing assistance and verified household income. Medicare administrative data are available through 2020. RESULTS: A total of 335,490 unique individuals who received housing assistance matched to SEER-Medicare data at any point in time, including 156,794 that recieved housing assistance around the time of their diagnosis (at least 6 months prior to diagnosis until 6 months after diagnosis or death). A total of 63,251 persons with housing assistance at the time of their diagnosis were aged 66 years and older and continuously enrolled in Medicare Parts A and B fee-for-service, 12,035 with lung, 8,866 with breast, 7,261 with colorectal, and 4,703 with prostate cancer. CONCLUSIONS: This novel data linkage will be available through the National Cancer Institute and can be used to explore the ways in which housing assistance is associated with cancer diagnosis, care, and outcomes, including the role of housing assistance status in potentially reducing or contributing to inequities across racialized and ethnic groups.

Use of Transesophageal Echocardiography for Liver Transplantation: A Global Comparison of Practice From the ILTS, SATA, and LICAGE.

BACKGROUND: Anesthesiologists frequently use intraoperative transesophageal echocardiography (TEE) to aid in the diagnosis and management of hemodynamic problems during liver transplantation (LT). Although the use of TEE in US centers continues to increase, data regarding international use are lacking. METHODS: This prospective, global, survey-based study evaluates international experience with TEE for LT. Responses from 252 LT (105 US and 147 non-US) centers representing 1789 anesthesiologists were analyzed. RESULTS: Routine use of TEE in the United States has increased in the last 5 y (from 37% to 47%), but only 21% of non-US LT anesthesiologists use TEE routinely. Lack of training (44% US versus 70% non-US) and equipment (9% non-US, versus 34% US) were cited as obstacles. Most survey participants preferred not to perform a complete cardiac examination but rather use only 6 of 11 basic views. Although non-US LT anesthesiologists more frequently had additional clinical training than their US counterparts, they had less TEE experience (13% versus 44%) and less frequently, TEE certification (22% versus 35%). Most LT anesthesiologists agreed that TEE certification is essential for proficiency. Of all respondents, 89% agreed or strongly agreed that TEE provides valuable information needed for immediate clinical decision-making, and >86% agreed or strongly agreed that that information could not be derived from other sources. CONCLUSIONS: The use of TEE for LT surgery in the US LT centers is currently higher compared with non-US LT centers. This may become a standard monitoring modality during LT in the near future.

Incisional negative pressure wound therapy may not protect against post-operative surgical site complications in bicondylar tibial plateau fractures.

PURPOSE: To determine if incisional negative pressure wound therapy is protective against post-operative surgical site complications following definitive fixation of bicondylar tibial plateau fractures. METHODS: A retrospective analysis of patients diagnosed with an acute bicondylar tibial plateau fracture (AO/OTA 41-C) undergoing ORIF from 2010 to 2020 was performed. Patients received either a standard sterile dressing (SD) or incisional negative pressure wound therapy (iNPWT). Primary outcomes included surgical site infection, osteomyelitis, and wound dehiscence. Secondary outcomes included non-union and return to the operating room. Multivariate logistic regression analyses were performed. RESULTS: 180 patients were included and 22% received iNPWT (n = 40) and 78% received standard dressings (n = 140). iNPWT was more common in active smokers (24.7% vs. 19.3%, p = 0.002) and the SD group was more likely to be lost to follow up (3.6% vs. 0%, p = 0.025). iNPWT was not protective against infection or surgical site complications, and in fact, was associated with higher odds of post-operative infection (OR: 8.96, p = 0.005) and surgical site complications (OR:4.874, p = 0.009) overall. Alcohol abuse (OR: 19, p = 0.005), tobacco use (OR: 4.67, p = 0.009), and time to definitive surgery (OR = 1.21, p = 0.033) were all independent risk factors for post-operative infection. CONCLUSION: In this series of operatively treated bicondylar tibial plateau fractures, iNPWT did not protect against post-operative surgical site complications compared to conventional dressings. Tobacco use, alcohol abuse, and time to definitive surgery, were independent risk factors for post-operative infection. Further studies are needed to determine if iNPWT offers a protective benefit in exclusively high-risk patients with relevant medical and social history.

Compassionomics: The Science and Practice of Caring.

PURPOSE: To summarize the scientific evidence that compassion can measurably improve patient outcomes, health care quality and safety, and the well-being of health care providers, and to consider specific strategies for cultivating compassion and better communicating it to patients. DESIGN: Perspective. METHODS: We selectively reviewed the literature on compassion in health care, including obstacles to its expression and the demonstrated effects of provider compassion on patient outcomes, health care quality and cost, and provider well-being. We also review evidence regarding the trainability of compassion, discuss proven methods for cultivating individual compassion, and recommend strategies for incorporating it into routine medical practice. RESULTS: Compassion is the emotional response to another's pain or suffering, accompanied by a desire to alleviate it. Review of the literature shows that compassionate health care measurably improves physical and psychological patient outcomes, increases patient adherence, improves health care quality and safety, increases financial margins, and prevents physician burnout. Psychophysiological research shows that empathy and compassion can be actively cultivated through intentional practice. Validated models of compassion-based interactions can facilitate the consistent expression of compassion in daily medical practice. CONCLUSIONS: Given its many proven benefits to patients, health care organizations, and providers, compassion should be cultivated by health care providers and systems and considered an essential component of optimal medical care.

Preliminary study on the stabilization of varus proximal femoral osteotomies using pediatric LCP plates in adults undergoing combined correction of proximal femoral and acetabular dysplasia.

PURPOSE: Proximal femoral osteotomy (PFO) with periacetabular osteotomy (PAO) improves femoral head coverage in patients with proximal femoral and acetabular dysplasia. Historically, blade plates used in the PFO cause soft-tissue irritation and often lead to implant removal. Here we present a technique using a lower profile pediatric proximal femoral locking compression plate (LCP) for the PFO in a series of adults. METHODS: The results from 13 hips in 11 patients ≥ 18 years old (age 18-37) with > 10 months of follow-up are presented. RESULTS: All patients had improved radiographic parameters, pain, and total Merle d'Aubigné-Postel scores postoperatively. Eleven hips (85%) had the LCP removed an average of 15.8 ± 8.6 months postoperatively, often due to pain over the greater trochanter. CONCLUSION: The pediatric proximal femoral LCP is effective for PFO in combined PAO PFO procedures but has a high rate of lateral hip discomfort leading to implant removal.

Expansion of highly interferon-responsive T cells in early-onset Alzheimer's disease.

INTRODUCTION: Altered immune signatures are emerging as a central theme in neurodegenerative disease, yet little is known about immune responses in early-onset Alzheimer's disease (EOAD). METHODS: We examined single-cell RNA-sequencing (scRNA-seq) data from peripheral blood mononuclear cells (PBMCs) and droplet digital (dd)PCR data from CD4 T cells from participants with EOAD and clinically normal controls. RESULTS: We analyzed ~182,000 PBMCs by scRNA-seq and discovered increased interferon signaling-associated gene (ISAG) expression and striking expansion of antiviral-like ISAGhi T cells in EOAD. We isolated CD4 T cells from additional EOAD cases and confirmed increased expression of ISAGhi marker genes. Publicly available cerebrospinal fluid leukocyte scRNA-seq data from late-onset mild cognitive impairment and AD also revealed increased expression of interferon-response genes. DISCUSSION: ISAGhi T cells, apparently primed for antiviral activity, are expanded in EOAD. Additional research into these cells and the role of heightened peripheral IFN signaling in neurodegeneration is warranted.

Effects of a True Prophylactic Treatment on Hippocampal and Amygdala Synaptic Plasticity and Gene Expression in a Rodent Chronic Stress Model of Social Defeat.

Post-traumatic stress disorder (PTSD) is a complex stress-related disorder induced by exposure to traumatic stress that is characterized by symptoms of re-experiencing, avoidance, and hyper-arousal. While it is widely accepted that brain regions involved in emotional regulation and memory-e.g., the amygdala and hippocampus-are dysregulated in PTSD, the pathophysiology of the disorder is not well defined and therefore, pharmacological interventions are extremely limited. Because stress hormones norepinephrine and cortisol (corticosterone in rats) are heavily implicated in the disorder, we explored whether preemptively and systemically antagonizing ß-adrenergic and glucocorticoid receptors with propranolol and mifepristone are sufficient to mitigate pathological changes in synaptic plasticity, gene expression, and anxiety induced by a modified social defeat (SD) stress protocol. Young adult, male Sprague Dawley rats were initially pre-screened for anxiety. The rats were then exposed to SD and chronic light stress to induce anxiety-like symptoms. Drug-treated rats were administered propranolol and mifepristone injections prior to and continuing throughout SD stress. Using competitive ELISAs on plasma, field electrophysiology at CA1 of the ventral hippocampus (VH) and the basolateral amygdala (BLA), quantitative RT-PCR, and behavior assays, we demonstrate that our SD stress increased anxiety-like behavior, elevated long-term potentiation (LTP) in the VH and BLA, and altered the expression of mineralocorticoid, glucocorticoid, and glutamate receptors. These measures largely reverted to control levels with the administration of propranolol and mifepristone. Our findings indicate that SD stress increases LTP in the VH and BLA and that prophylactic treatment with propranolol and mifepristone may have the potential in mitigating these and other stress-induced effects.

Single-cell RNA-seq reveals alterations in peripheral CX3CR1 and nonclassical monocytes in familial tauopathy.

BACKGROUND: Emerging evidence from mouse models is beginning to elucidate the brain's immune response to tau pathology, but little is known about the nature of this response in humans. In addition, it remains unclear to what extent tau pathology and the local inflammatory response within the brain influence the broader immune system. METHODS: To address these questions, we performed single-cell RNA sequencing (scRNA-seq) of peripheral blood mononuclear cells (PBMCs) from carriers of pathogenic variants in MAPT, the gene encoding tau (n = 8), and healthy non-carrier controls (n = 8). Primary findings from our scRNA-seq analyses were confirmed and extended via flow cytometry, droplet digital (dd)PCR, and secondary analyses of publicly available transcriptomics datasets. RESULTS: Analysis of ~ 181,000 individual PBMC transcriptomes demonstrated striking differential expression in monocytes and natural killer (NK) cells in MAPT pathogenic variant carriers. In particular, we observed a marked reduction in the expression of CX3CR1-the gene encoding the fractalkine receptor that is known to modulate tau pathology in mouse models-in monocytes and NK cells. We also observed a significant reduction in the abundance of nonclassical monocytes and dysregulated expression of nonclassical monocyte marker genes, including FCGR3A. Finally, we identified reductions in TMEM176A and TMEM176B, genes thought to be involved in the inflammatory response in human microglia but with unclear function in peripheral monocytes. We confirmed the reduction in nonclassical monocytes by flow cytometry and the differential expression of select biologically relevant genes dysregulated in our scRNA-seq data using ddPCR. CONCLUSIONS: Our results suggest that human peripheral immune cell expression and abundance are modulated by tau-associated pathophysiologic changes. CX3CR1 and nonclassical monocytes in particular will be a focus of future work exploring the role of these peripheral signals in additional tau-associated neurodegenerative diseases.

Retinoic acid is dispensable for meiotic initiation but required for spermiogenesis in the mammalian testis.

Retinoic acid (RA) is the proposed mammalian 'meiosis inducing substance'. However, evidence for this role comes from studies in the fetal ovary, where germ cell differentiation and meiotic initiation are temporally inseparable. In the postnatal testis, these events are separated by more than 1 week. Exploiting this difference, we discovered that, although RA is required for spermatogonial differentiation, it is dispensable for the subsequent initiation, progression and completion of meiosis. Indeed, in the absence of RA, the meiotic transcriptome program in both differentiating spermatogonia and spermatocytes entering meiosis was largely unaffected. Instead, transcripts encoding factors required during spermiogenesis were aberrant during preleptonema, and the subsequent spermatid morphogenesis program was disrupted such that no sperm were produced. Taken together, these data reveal a RA-independent model for male meiotic initiation.

Trends in Female Authorship in Orthopaedic Literature from 2002 to 2021: An Analysis of 168,451 Authors.

BACKGROUND: Significant gender disparity exists in orthopaedic surgery. While women have increasingly entered the field, we are short of the critical mass needed to drive change, including in authorship. This study aimed to characterize trends in authorship in peer-reviewed orthopaedic journals in the context of gender. METHODS: This is a cross-sectional bibliometric study of orthopaedic journals in the United States. Articles that were indexed in the orthopaedic category of the Clarivate Journal Citation Report (JCR) and the Science Citation Index Expanded (SCIE) were analyzed (n = 82). Journals not originating from the U.S. (n = 43) or not considered primarily orthopaedic journals (n = 13) were excluded. The 2020 impact factors (IFs) of the remaining 26 journals were recorded. The articles underwent automated data collection from PubMed for January 2002 to December 2021 using R software to collect the title, the journal, the publication year, the first and senior author names, and the country of origin. Gender was determined by Gender API ( https://gender-api.com ). Names with <90% accuracy were excluded. RESULTS: Overall, 168,451 names were studied, with 85,845 and 82,606 first and senior authors, respectively. Of the first and senior authors, 13.6% and 9.9%, respectively, were female. The proportion of female first authors was significantly greater than the proportion of female senior authors. The average IF was significantly higher for male authors compared with female authors (p < 0.005). Articles with female first authors were significantly more likely to have a female senior author. Orthopaedic subspecialty journals had a smaller proportion of manuscripts authored by female first and senior authors than general journals (p < 0.0001). There were 4,451 articles written by a single author, of which 92% (4,093) were written by a man and 8% (358) were written by a woman. Over the 20-year study period, the proportion of female first authorship exhibited a significant positive trend; however, there was a non-significant increase in female senior authorship. CONCLUSIONS: Female representation in orthopaedics has been growing over the past decade. Increasing publication rates of female authors reveal steps toward positive gender equity in the field and present an opportunity for female leadership visibility, illustrating the capabilities of women in orthopaedics and encouraging more women to join the field.

Cutibacterium (Formerly Propionibacterium ) acnes Keratitis: A Review.

ABSTRACT: Infectious keratitis is a devastating cause of vision loss worldwide. Cutibacterium acnes ( C. acnes ), a commensal bacterium of the skin and ocular surface, is an underrecognized but important cause of bacterial keratitis. This review presents the most comprehensive and up-to-date information for clinicians regarding the risk factors, incidence, diagnosis, management, and prognosis of C. acnes keratitis (CAK). Risk factors are similar to those of general bacterial keratitis and include contact lens use, past ocular surgery, and trauma. The incidence of CAK may be approximately 10%, ranging from 5% to 25% in growth-positive cultures. Accurate diagnosis requires anaerobic blood agar and a long incubation period (≥7 days). Typical clinical presentation includes small (<2 mm) ulcerations with deep stromal infiltrate causing an anterior chamber cell reaction. Small, peripheral lesions are usually resolved, and patients recover a high visual acuity. Severe infections causing VA of 20/200 or worse are common and often do not significantly improve even after treatment. Vancomycin is considered the most potent antibiotic against CAK, although other antibiotics such as moxifloxacin and ceftazidime are more commonly used as first-line treatment.

Introduction of a Novel Sequential Approach to the Ponte Osteotomy to Minimize Spinal Canal Exposure.

Ponte osteotomy is an increasingly popular technique for multiplanar correction of adolescent idiopathic scoliosis. Prior cadaveric studies have suggested that sequential posterior spinal releases increase spinal flexibility. Here we introduce a novel technique involving a sequential approach to the Ponte osteotomy that minimizes spinal canal exposure. One fresh-frozen adult human cadaveric thoracic spine specimen with 4 cm of ribs was divided into three sections (T1-T5, T6-T9, T10-L1) and mounted for biomechanical testing. Each segment was loaded with five Newton meters under four conditions: baseline inferior facetectomy with supra/interspinous ligament release, superior articular process (SAP) osteotomy in situ, spinous process (SP) osteotomy in situ, and complete posterior column osteotomy with SP/SAP excision and ligamentum flavum release (PCO). Compared to baseline, in situ SAP osteotomy alone provided 3.5%, 7.6%, and 7.2% increase in flexion/extension, lateral bending, and axial rotation, respectively. In situ SP osteotomy increased flexion/extension, lateral bending, and axial rotation by 15%, 18%, and 10.3%, respectively. PCO increased flexion/extension, lateral bending, and axial rotation by 19.6%, 28.3%, and 12.2%, respectively. Our report introduces a novel approach where incremental increases in range of motion can be achieved with minimal spinal canal exposure and demonstrates feasibility in a cadaveric model.

Differential responsiveness of spermatogonia to retinoic acid dictates precocious differentiation but not meiotic entry during steady-state spermatogenesis†.

The foundation of mammalian spermatogenesis is provided by undifferentiated spermatogonia, which comprise of spermatogonial stem cells (SSCs) and transit-amplifying progenitors that differentiate in response to retinoic acid (RA) and are committed to enter meiosis. Our laboratory recently reported that the foundational populations of SSCs, undifferentiated progenitors, and differentiating spermatogonia are formed in the neonatal testis in part based on their differential responsiveness to RA. Here, we expand on those findings to define the extent to which RA responsiveness during steady-state spermatogenesis in the adult testis regulates the spermatogonial fate. Our results reveal that both progenitor and differentiating spermatogonia throughout the testis are capable of responding to exogenous RA, but their resulting fates were quite distinct-undifferentiated progenitors precociously differentiated and proceeded into meiosis on a normal timeline, while differentiating spermatogonia were unable to hasten their entry into meiosis. This reveals that the spermatogonia responding to RA must still complete the 8.6 day differentiation program prior to their entry into meiosis. Addition of exogenous RA enriched testes with preleptotene and pachytene spermatocytes one and two seminiferous cycles later, respectively, supporting recent clinical studies reporting increased sperm production and enhanced fertility in subfertile men on long-term RA analog treatment. Collectively, our results reveal that a well-buffered system exists within mammalian testes to regulate spermatogonial RA exposure, that exposed undifferentiated progenitors can precociously differentiate, but must complete a normal-length differentiation program prior to entering meiosis, and that daily RA treatments increased the numbers of advanced germ cells by directing undifferentiated progenitors to continuously differentiate.

Phytochemical compound PB125 attenuates skeletal muscle mitochondrial dysfunction and impaired proteostasis in a model of musculoskeletal decline.

Impaired mitochondrial function and disrupted proteostasis contribute to musculoskeletal dysfunction. However, few interventions simultaneously target these two drivers to prevent musculoskeletal decline. Nuclear factor erythroid 2-related factor 2 (Nrf2) activates a transcriptional programme promoting cytoprotection, metabolism, and proteostasis. We hypothesized daily treatment with a purported Nrf2 activator, PB125, in Hartley guinea pigs, a model of musculoskeletal decline, would attenuate the progression of skeletal muscle mitochondrial dysfunction and impaired proteostasis and preserve musculoskeletal function. We treated 2- and 5-month-old male and female Hartley guinea pigs for 3 and 10 months, respectively, with the phytochemical compound PB125. Longitudinal assessments of voluntary mobility were measured using Any-MazeTM open-field enclosure monitoring. Cumulative skeletal muscle protein synthesis rates were measured using deuterium oxide over the final 30 days of treatment. Mitochondrial oxygen consumption in soleus muscles was measured using high resolution respirometry. In both sexes, PB125 (1) increased electron transfer system capacity; (2) attenuated the disease/age-related decline in coupled and uncoupled mitochondrial respiration; and (3) attenuated declines in protein synthesis in the myofibrillar, mitochondrial and cytosolic subfractions of the soleus. These effects were not associated with statistically significant prolonged maintenance of voluntary mobility in guinea pigs. Collectively, treatment with PB125 contributed to maintenance of skeletal muscle mitochondrial respiration and proteostasis in a pre-clinical model of musculoskeletal decline. Further investigation is necessary to determine if these documented effects of PB125 are also accompanied by slowed progression of other aspects of musculoskeletal dysfunction. KEY POINTS: Aside from exercise, there are no effective interventions for musculoskeletal decline, which begins in the fifth decade of life and contributes to disability and cardiometabolic diseases. Targeting both mitochondrial dysfunction and impaired protein homeostasis (proteostasis), which contribute to the age and disease process, may mitigate the progressive decline in overall musculoskeletal function (e.g. gait, strength). A potential intervention to target disease drivers is to stimulate nuclear factor erythroid 2-related factor 2 (Nrf2) activation, which leads to the transcription of genes responsible for redox homeostasis, proteome maintenance and mitochondrial energetics. Here, we tested a purported phytochemical Nrf2 activator, PB125, to improve mitochondrial function and proteostasis in male and female Hartley guinea pigs, which are a model for musculoskeletal ageing. PB125 improved mitochondrial respiration and attenuated disease- and age-related declines in skeletal muscle protein synthesis, a component of proteostasis, in both male and female Hartley guinea pigs.

Self-care can be an alternative to expand access to universal health care: What policy makers, governments and implementers can consider for South Africa.

As a result of collaboration amongst the various decision-makers in the field of healthcare, there has been an improvement in the access to healthcare and living conditions globally. Nonetheless, poorer communities continue to benefit the least from public investment. To bridge the gap, self-care can be a viable alternative as it allows individuals and communities to reduce their dependence on government healthcare solutions. Barriers to self-care do exist. Some of these are cost effectiveness, usability of self-care instruments, differentiated strategies and linkage to care. In identifying these obstacles, it is also worthwhile to investigate how they can be mitigated. To encourage sustained self-care in the HIV continuum, contextual factors as well as the manner in which individuals and communities engage with self-care must be considered. In South Africa, multiple variables come into play: literacy levels, cultural influences, socio-economic conditions and access to resources are some of these. Evidence demonstrates how self-care can be promoted by various stakeholders re-strategising to tweak and in some cases totally change existing structures. This paper explores some of the transformations, like at a governmental level where the supply of HIV self-testing kits is increased, at a production level where instructions for use are reformatting, in communities where sports programmes fulfil the dual purpose of developing sport skills and providing HIV education concurrently, and at an individual level where greater awareness invites greater participation in self-care. While self-care is a promising proposal, it is not a replacement for traditional health-care practices, but a complementary approach.

Reply to Correspondence on "Synergy and Antagonism between Allosteric and Active-Site Inhibitors of Abl Tyrosine Kinase".

Manley and co-workers provide data demonstrating that, at super-pharmacological concentrations (300 µM), a ternary complex between Abl, asciminib, and ATP-competitive inhibitors is possible. The work in our manuscript concerns the interplay of asciminib (and GNF-2) with ATP-competitive inhibitors at pharmacologically relevant concentrations (Cmax =1.6-3.7 µM for asciminib). Manley and co-workers do not question any of the studies that we reported, nor do they provide explanations for how our work fits into their preferred model. Herein, we consider the data presented by Manley and co-workers. In addition, we provide new data supporting the findings in our Communication. Asciminib and ATP-competitive inhibitors do not simultaneously bind Abl at pharmacologically relevant concentrations unless the conformation selectivity for both ligands is matched.

Modeling mammalian spermatogonial differentiation and meiotic initiation in vitro.

In mammalian testes, premeiotic spermatogonia respond to retinoic acid by completing an essential lengthy differentiation program before initiating meiosis. The molecular and cellular changes directing these developmental processes remain largely undefined. This wide gap in knowledge is due to two unresolved technical challenges: (1) lack of robust and reliable in vitro models to study differentiation and meiotic initiation; and (2) lack of methods to isolate large and pure populations of male germ cells at each stage of differentiation and at meiotic initiation. Here, we report a facile in vitro differentiation and meiotic initiation system that can be readily manipulated, including the use of chemical agents that cannot be safely administered to live animals. In addition, we present a transgenic mouse model enabling fluorescence-activated cell sorting-based isolation of millions of spermatogonia at specific developmental stages as well as meiotic spermatocytes.

The germ cell-specific RNA binding protein RBM46 is essential for spermatogonial differentiation in mice.

Control over gene expression is exerted, in multiple stages of spermatogenesis, at the post-transcriptional level by RNA binding proteins (RBPs). We identify here an essential role in mammalian spermatogenesis and male fertility for 'RNA binding protein 46' (RBM46). A highly evolutionarily conserved gene, Rbm46 is also essential for fertility in both flies and fish. We found Rbm46 expression was restricted to the mouse germline, detectable in males in the cytoplasm of premeiotic spermatogonia and meiotic spermatocytes. To define its requirement for spermatogenesis, we generated Rbm46 knockout (KO, Rbm46-/-) mice; although male Rbm46-/- mice were viable and appeared grossly normal, they were infertile. Testes from adult Rbm46-/- mice were small, with seminiferous tubules containing only Sertoli cells and few undifferentiated spermatogonia. Using genome-wide unbiased high throughput assays RNA-seq and 'enhanced crosslinking immunoprecipitation' coupled with RNA-seq (eCLIP-seq), we discovered RBM46 could bind, via a U-rich conserved consensus sequence, to a cohort of mRNAs encoding proteins required for completion of differentiation and subsequent meiotic initiation. In summary, our studies support an essential role for RBM46 in regulating target mRNAs during spermatogonia differentiation prior to the commitment to meiosis in mice.

Dissecting the clinical heterogeneity of early-onset Alzheimer's disease.

Early-onset Alzheimer's disease (EOAD) is a rare but particularly devastating form of AD. Though notable for its high degree of clinical heterogeneity, EOAD is defined by the same neuropathological hallmarks underlying the more common, late-onset form of AD. In this review, we describe the various clinical syndromes associated with EOAD, including the typical amnestic phenotype as well as atypical variants affecting visuospatial, language, executive, behavioral, and motor functions. We go on to highlight advances in fluid biomarker research and describe how molecular, structural, and functional neuroimaging can be used not only to improve EOAD diagnostic acumen but also enhance our understanding of fundamental pathobiological changes occurring years (and even decades) before the onset of symptoms. In addition, we discuss genetic variation underlying EOAD, including pathogenic variants responsible for the well-known mendelian forms of EOAD as well as variants that may increase risk for the much more common forms of EOAD that are either considered to be sporadic or lack a clear autosomal-dominant inheritance pattern. Intriguingly, specific pathogenic variants in PRNP and MAPT-genes which are more commonly associated with other neurodegenerative diseases-may provide unexpectedly important insights into the formation of AD tau pathology. Genetic analysis of the atypical clinical syndromes associated with EOAD will continue to be challenging given their rarity, but integration of fluid biomarker data, multimodal imaging, and various 'omics techniques and their application to the study of large, multicenter cohorts will enable future discoveries of fundamental mechanisms underlying the development of EOAD and its varied clinical presentations.