Crosstalk between muscularis macrophages and enteric neurons regulates gastrointestinal motility.

Intestinal peristalsis is a dynamic physiologic process influenced by dietary and microbial changes. It is tightly regulated by complex cellular interactions; however, our understanding of these controls is incomplete. A distinct population of macrophages is distributed in the intestinal muscularis externa. We demonstrate that, in the steady state, muscularis macrophages regulate peristaltic activity of the colon. They change the pattern of smooth muscle contractions by secreting bone morphogenetic protein 2 (BMP2), which activates BMP receptor (BMPR) expressed by enteric neurons. Enteric neurons, in turn, secrete colony stimulatory factor 1 (CSF1), a growth factor required for macrophage development. Finally, stimuli from microbial commensals regulate BMP2 expression by macrophages and CSF1 expression by enteric neurons. Our findings identify a plastic, microbiota-driven crosstalk between muscularis macrophages and enteric neurons that controls gastrointestinal motility. PAPERFLICK:

Spatial profiling of early primate gastrulation in utero.

Gastrulation controls the emergence of cellular diversity and axis patterning in the early embryo. In mammals, this transformation is orchestrated by dynamic signalling centres at the interface of embryonic and extraembryonic tissues1-3. Elucidating the molecular framework of axis formation in vivo is fundamental for our understanding of human development4-6 and to advance stem-cell-based regenerative approaches7. Here we illuminate early gastrulation of marmoset embryos in utero using spatial transcriptomics and stem-cell-based embryo models. Gaussian process regression-based 3D transcriptomes delineate the emergence of the anterior visceral endoderm, which is hallmarked by conserved (HHEX, LEFTY2, LHX1) and primate-specific (POSTN, SDC4, FZD5) factors. WNT signalling spatially coordinates the formation of the primitive streak in the embryonic disc and is counteracted by SFRP1 and SFRP2 to sustain pluripotency in the anterior domain. Amnion specification occurs at the boundaries of the embryonic disc through ID1, ID2 and ID3 in response to BMP signalling, providing a developmental rationale for amnion differentiation of primate pluripotent stem cells (PSCs). Spatial identity mapping demonstrates that primed marmoset PSCs exhibit the highest similarity to the anterior embryonic disc, whereas naive PSCs resemble the preimplantation epiblast. Our 3D transcriptome models reveal the molecular code of lineage specification in the primate embryo and provide an in vivo reference to decipher human development.

Advancing interdisciplinary science for disrupting wildlife trafficking networks.

Wildlife trafficking, whether local or transnational in scope, undermines sustainable development efforts, degrades cultural resources, endangers species, erodes the local and global economy, and facilitates the spread of zoonotic diseases. Wildlife trafficking networks (WTNs) occupy a unique gray space in supply chains-straddling licit and illicit networks, supporting legitimate and criminal workforces, and often demonstrating high resilience in their sourcing flexibility and adaptability. Authorities in different sectors desire, but frequently lack knowledge about how to allocate resources to disrupt illicit wildlife supply networks and prevent negative collateral impacts. Novel conceptualizations and a deeper scientific understanding of WTN structures are needed to help unravel the dynamics of interaction between disruption and resilience while accommodating socioenvironmental context. We use the case of ploughshare tortoise trafficking to help illustrate the potential of key advancements in interdisciplinary thinking. Insights herein suggest a significant need and opportunity for scientists to generate new science-based recommendations for WTN-related data collection and analysis for supply chain visibility, shifts in illicit supply chain dominance, network resilience, or limits of the supplier base.

Colony stimulating factors in the nervous system.

Although traditionally seen as regulators of hematopoiesis, colony-stimulating factors (CSFs) have emerged as important players in the nervous system, both in health and disease. This review summarizes the cellular sources, patterns of expression and physiological roles of the macrophage (CSF-1, IL-34), granulocyte-macrophage (GM-CSF) and granulocyte (G-CSF) colony stimulating factors within the nervous system, with a particular focus on their actions on microglia. CSF-1 and IL-34, via the CSF-1R, are required for the development, proliferation and maintenance of essentially all CNS microglia in a temporal and regional specific manner. In contrast, in steady state, GM-CSF and G-CSF are mainly involved in regulation of microglial function. The alterations in expression of these growth factors and their receptors, that have been reported in several neurological diseases, are described and the outcomes of their therapeutic targeting in mouse models and humans are discussed.

Pharmacologic Drug Detection and Self-Reported Adherence in the HPTN069/ACTG5305 Phase II PrEP Trial.

Adherence drives efficacy in PrEP clinical trials. We compared drug concentrations and self-reported adherence in HPTN069/ACTG5305, a double-blinded, randomized trial of the safety and tolerability of candidate PrEP regimens that included maraviroc (MVC), tenofovir (TDF), and emtricitabine (FTC). Plasma drug concentrations and self-reported adherence by computer-assisted self-interview (CASI) were assessed at study weeks 24 and 48. Descriptive statistics and a generalized linear model were used to assess the association between selected demographic factors, self-report of daily medication adherence and plasma drug concentrations consistent with daily adherence. Among 718 paired observations from 370 participants, 43% (306/718) reported daily adherence by CASI, 65% (467/718) had drug concentrations consistent with daily adherence and 11% (81/718) had CASI responses that reported daily adherence despite having drug concentrations consistent with less-than-daily adherence. In adjusted analyses, participants who were assigned male at birth (aOR 1.42 [95% CI 1.02, 1.97]), older (5-year increments aOR 1.10 [95% CI 1.09, 1.11]), White (aOR 2.2 [95% CI 1.88, 2.56]), had advanced education (aOR 3.89 [95% CI 2.97, 5.09]), were employed (aOR 1.89 [95% CI 1.50, 2.40]), or partnered/married (aOR 2 [95% CI 1.72, 2.32]) were more likely to have drug concentrations consistent with daily adherence. Participants who were not employed (aOR 2.7 [95% CI 1.31, 5.55]) or who were single/not partnered (aOR 2.33 [CI 95% 1.25, 4.34]) were more likely to have drug concentrations that did not reflect daily adherence despite self-reported PrEP adherence. These findings support the need for ongoing adherence counseling in clinical trials of new PrEP regimens.

Attention and neurodevelopment in young children who are HIV-exposed uninfected.

ABSTRACTChildren HIV-exposed, uninfected (CHEU) are at risk for compromised developmental outcomes. Attention is important for behavioural, cognitive and academic skills, yet has not been thoroughly investigated compared to children HIV-unexposed uninfected (CHUU). Fifty-five CHEU and 51 CHUU children were recruited at 5.5 years of age. Measures of inattention (IA), hyperactivity/impulsivity (HI) and total scores were collected using the parent-reported ADHD-Rating-Scale-IV. Measures of intelligence, visuomotor skills, academics and adaptive functioning were obtained. Analyses of between-group differences were performed as were correlational and multiple regression models, accounting for maternal education, employment and delivery type. Few children met clinical cut-offs for probable ADHD (3.6% CHEU, 2.0% CHUU), and no group differences in measures of IA, HI and combined scores were found. CHEU scored significantly lower than CHUU on intelligence, visuomotor function, academic skills and aspects of adaptive behaviour, though within age expectations. Lower Full-Scale IQ and Processing Speed were associated with higher IA in CHEU and lower adaptive functioning with higher IA in CHUU. Across both groups, children of unemployed mothers had more HI symptoms. CHEU were not at increased risk for attention difficulties at 5.5 years of age. Maternal employment status highlights the contribution of sociodemographic factors in shaping behaviour and neurodevelopment.

OCT4 induces embryonic pluripotency via STAT3 signaling and metabolic mechanisms.

OCT4 is a fundamental component of the molecular circuitry governing pluripotency in vivo and in vitro. To determine how OCT4 establishes and protects the pluripotent lineage in the embryo, we used comparative single-cell transcriptomics and quantitative immunofluorescence on control and OCT4 null blastocyst inner cell masses at two developmental stages. Surprisingly, activation of most pluripotency-associated transcription factors in the early mouse embryo occurs independently of OCT4, with the exception of the JAK/STAT signaling machinery. Concurrently, OCT4 null inner cell masses ectopically activate a subset of trophectoderm-associated genes. Inspection of metabolic pathways implicates the regulation of rate-limiting glycolytic enzymes by OCT4, consistent with a role in sustaining glycolysis. Furthermore, up-regulation of the lysosomal pathway was specifically detected in OCT4 null embryos. This finding implicates a requirement for OCT4 in the production of normal trophectoderm. Collectively, our findings uncover regulation of cellular metabolism and biophysical properties as mechanisms by which OCT4 instructs pluripotency.

Genetic loci associated with skin pigmentation in African Americans and their effects on vitamin D deficiency.

A recent genome-wide association study (GWAS) in African descent populations identified novel loci associated with skin pigmentation. However, how genomic variations affect skin pigmentation and how these skin pigmentation gene variants affect serum 25(OH) vitamin D variation has not been explored in African Americans (AAs). In order to further understand genetic factors that affect human skin pigmentation and serum 25(OH)D variation, we performed a GWAS for skin pigmentation with 395 AAs and a replication study with 681 AAs. Then, we tested if the identified variants are associated with serum 25(OH) D concentrations in a subset of AAs (n = 591). Skin pigmentation, Melanin Index (M-Index), was measured using a narrow-band reflectometer. Multiple regression analysis was performed to identify variants associated with M-Index and to assess their role in serum 25(OH)D variation adjusting for population stratification and relevant confounding variables. A variant near the SLC24A5 gene (rs2675345) showed the strongest signal of association with M-Index (P = 4.0 x 10-30 in the pooled dataset). Variants in SLC24A5, SLC45A2 and OCA2 together account for a large proportion of skin pigmentation variance (11%). The effects of these variants on M-Index was modified by sex (P for interaction = 0.009). However, West African Ancestry (WAA) also accounts for a large proportion of M-Index variance (23%). M-Index also varies among AAs with high WAA and high Genetic Score calculated from top variants associated with M-Index, suggesting that other unknown genomic factors related to WAA are likely contributing to skin pigmentation variation. M-Index was not associated with serum 25(OH)D concentrations, but the Genetic Score was significantly associated with vitamin D deficiency (serum 25(OH)D levels less than 12 ng/mL) (OR, 1.30; 95% CI, 1.04-1.64). The findings support the hypothesis suggesting that skin pigmentation evolved responding to increased demand for subcutaneous vitamin D synthesis in high latitude environments.

Three-dimensionally printed osteotomy and reaming guides for correction of a multiplanar femoral deformity stabilized with an interlocking nail in a dog.

OBJECTIVE: To describe the use of virtual surgical planning (VSP) and three-dimensionally (3D) printed surgical guides for corrective osteotomies stabilized with an interlocking nail in a dog with a multiplanar femoral deformity. STUDY DESIGN: Case report. ANIMALS: An 8-year-old male neutered mixed breed dog weighing 44 kg. METHODS: A dog was presented for a right grade 3 lateral patellar luxation secondary to a multiplanar femoral deformity due to a suspected femoral malunion. A computed tomography (CT) scan was obtained to create virtual femoral models. Corrective osteotomies were simulated with VSP. Custom osteotomy guides and reaming guides were designed to facilitate the correction and the placement of an interlocking nail. The preoperative femoral model, virtually aligned femoral model, custom osteotomy guides, and reaming guides were 3D printed, sterilized, and utilized intraoperatively. A CT scan was performed postoperatively to assess femoral length and alignment. RESULTS: Custom osteotomy and reaming guides were used as intended by the VSP. Postoperative femoral length as well as frontal, sagittal, and axial plane alignment were within 0.7 mm, 2.2°, 0.5°, and 1.6°, respectively, of the virtually planned femoral model. Two months postoperatively, the dog was sound on visual gait examination, and the patella tracked in the trochlear groove throughout stifle range of motion and was unable to be manually luxated. Radiographs obtained 2 months postoperatively revealed static femoral alignment and implants. Both osteotomies were discernable with callus bridging. CONCLUSION: Virtual surgical planning and custom osteotomy and reaming guides facilitated complex femoral corrective osteotomies and interlocking nail placement.

Virtual surgical planning and use of a 3D-printed, patient-specific reduction system for minimally invasive plate osteosynthesis of diaphyseal tibial fractures in dogs: A historic case control study.

OBJECTIVE: To compare the efficacy and clinical outcomes of computed tomography (CT)-based virtual surgical planning (VSP) and a three-dimensional (3D)-printed, patient-specific reduction system to conventional indirect reduction techniques for diaphyseal tibial fractures stabilized using minimally invasive plate osteosynthesis (MIPO) in dogs. STUDY DESIGN: A prospective clinical study with a historic control cohort. SAMPLE POPULATION: Dogs undergoing MIPO stabilization of diaphyseal tibial fractures using a custom 3D-printed reduction system (3D-MIPO; n = 15) or conventional indirect reduction techniques (c-MIPO; n = 14). METHODS: Dogs were prospectively enrolled to the 3D-MIPO group and CT scans were used to design and fabricate a custom 3D-printed reduction system to facilitate MIPO. Medical records were searched to identify dogs for the c-MIPO group. Pre-, intra- and postoperative parameters were compared between groups. RESULTS: The duration from presentation until surgery was 23 h longer in the 3D-MIPO group (p = .002). Fewer intraoperative fluoroscopic images were acquired (p < .001) and mean surgical duration was 34 min shorter in the 3D-MIPO group (p = .014). Median postoperative tibial length, frontal alignment, and sagittal alignment were within 4 mm, 3° and 3°, respectively, of the contralateral tibia in both groups and did not differ between reduction groups (p > .1). Postoperative complications occurred in 27% and 14% of fractures in the 3D-MIPO and c-MIPO groups, respectively. CONCLUSION: Both reduction methods yielded comparable results. Although the preoperative planning and guide preparation was time consuming, surgery times were shorter and fluoroscopy use was less in the 3D-MIPO group. CLINICAL SIGNIFICANCE: VSP and the custom 3D-printed reduction system facilitated efficient MIPO.

Efficacy of virtual surgical planning and a three-dimensional-printed, patient-specific reduction system to facilitate alignment of diaphyseal tibial fractures stabilized by minimally invasive plate osteosynthesis in dogs: A prospective clinical study.

OBJECTIVE: To evaluate the efficacy of a three-dimensional (3D)-printed, patient-specific reduction system for aligning diaphyseal tibial fractures stabilized using minimally invasive plate osteosynthesis (MIPO). STUDY DESIGN: Prospective clinical trial. SAMPLE POPULATION: Fifteen client owned dogs. METHODS: Virtual 3D models of both pelvic limbs were created. Pin guides were designed to conform to the proximal and distal tibia. A reduction bridge was designed to align the pin guides based on the guides' spatial location. Guides were 3D printed, sterilized, and applied, in conjunction with transient application of a circular fixator, to facilitate indirect fracture realignment before plate application. Alignment of the stabilized tibiae was assessed using postoperative computed tomography scans. RESULTS: Mean duration required for virtual planning was 2.5 h and a mean of 50.7 h elapsed between presentation and surgery. Guide placement was accurate with minor median discrepancies in translation and frontal, sagittal, and axial plane positioning of 2.9 mm, 3.6°, 2.7°, and 6.8°, respectively. Application of the reduction system restored mean tibial length and frontal, sagittal, and axial alignment within 1.7 mm, 1.9°, 1.7°, and 4.5°, respectively, of the contralateral tibia. CONCLUSION: Design and fabrication of a 3D-printed, patient-specific fracture reduction system is feasible in a relevant clinical timeline. Intraoperative pin-guide placement was reasonably accurate with minor discrepancies compared to the virtual plan. Custom 3D-printed reduction system application facilitated near-anatomic or acceptable fracture reduction in all dogs. CLINICAL SIGNIFICANCE: Virtual planning and fabrication of a 3D-printing patient-specific fracture reduction system is practical and facilitated acceptable, if not near-anatomic, fracture alignment during MIPO.

Prophylactic effect of chronic immunosuppression in a mouse model of CSF-1 receptor-related leukoencephalopathy.

Mutations leading to colony-stimulating factor-1 receptor (CSF-1R) loss-of-function or haploinsufficiency cause CSF1R-related leukoencephalopathy (CRL), an adult-onset disease characterized by loss of myelin and neurodegeneration, for which there is no effective therapy. Symptom onset usually occurs in the fourth decade of life and the penetrance of disease in carriers is high. However, familial studies have identified a few carriers of pathogenic CSF1R mutations that remain asymptomatic even in their seventh decade of life, raising the possibility that the development and severity of disease might be influenced by environmental factors. Here we report new cases in which long-term glucocorticoid treatment is associated with asymptomatic status in elder carriers of pathogenic CSF-1R mutations. The main objective of the present study was to investigate the link between chronic immunosuppression initiated pre-symptomatically and resistance to the development of symptomatic CRL, in the Csf1r+/- mouse model. We show that chronic prednisone administration prevents the development of memory, motor coordination and social interaction deficits, as well as the demyelination, neurodegeneration and microgliosis associated with these deficits. These findings are in agreement with the preliminary clinical observations and support the concept that pre-symptomatic immunosuppression is protective in patients carrying pathogenic CSF1R variants associated with CRL. Proteomic analysis of microglia and oligodendrocytes indicates that prednisone suppresses processes involved in microglial activation and alleviates senescence and improves fitness of oligodendrocytes. This analysis also identifies new potential targets for therapeutic intervention.

Elevated granulocyte colony stimulating factor (CSF) causes cerebellar deficits and anxiety in a model of CSF-1 receptor related leukodystrophy.

Colony stimulating factor (CSF) receptor-1 (CSF-1R)-related leukoencephalopathy (CRL) is an adult-onset, demyelinating and neurodegenerative disease caused by autosomal dominant mutations in CSF1R, modeled by the Csf1r+/- mouse. The expression of Csf2, encoding granulocyte-macrophage CSF (GM-CSF) and of Csf3, encoding granulocyte CSF (G-CSF), are elevated in both mouse and human CRL brains. While monoallelic targeting of Csf2 has been shown to attenuate many behavioral and histological deficits of Csf1r+/- mice, including cognitive dysfunction and demyelination, the contribution of Csf3 has not been explored. In the present study, we investigate the behavioral, electrophysiological and histopathological phenotypes of Csf1r+/- mice following monoallelic targeting of Csf3. We show that Csf3 heterozygosity normalized the Csf3 levels in Csf1r+/- mouse brains and ameliorated anxiety-like behavior, motor coordination and social interaction deficits, but not the cognitive impairment of Csf1r+/- mice. Csf3 heterozygosity failed to prevent callosal demyelination. However, consistent with its effects on behavior, Csf3 heterozygosity normalized microglial morphology in the cerebellum and in the ventral, but not in the dorsal hippocampus. Csf1r+/- mice exhibited altered firing activity in the deep cerebellar nuclei (DCN) associated with increased engulfment of glutamatergic synapses by DCN microglia and increased deposition of the complement factor C1q on glutamatergic synapses. These phenotypes were significantly ameliorated by monoallelic deletion of Csf3. Our current and earlier findings indicate that G-CSF and GM-CSF play largely non-overlapping roles in CRL-like disease development in Csf1r+/- mice.

A systematic review and meta-analysis of sirolimus-eluting stents for treatment of below-the-knee arterial disease.

OBJECTIVE: We performed a systematic review and meta-analysis to analyze the efficacy and safety of sirolimus-eluting stents (SESs) in the treatment of below-the-knee (BTK) arterial disease. METHODS: An electronic literature search was conducted from inception to July 24, 2021. Retrospective, prospective, and randomized studies that had used SESs to treat BTK arterial disease and had reported the primary patency, technical success, target lesion revascularization, and/or mortality were included. Meta-analyses of the proportions were conducted to derive pooled summary statistics of the outcomes. Where Kaplan-Meier curves were provided for primary patency, a meta-analysis of the individual patient data was conducted via a graphic reconstruction tool to estimate primary patency at various follow-up points. For studies comparing SESs and bare metal stents (BMSs), a two-stage meta-analysis was performed to compare the 6-month primary patency of SESs vs BMSs. RESULTS: Ten studies across 13 publications, including 995 patients, were retrieved for analysis. In the meta-analysis of proportions, across six studies (n = 339 patients), the pooled 6-month primary patency was 87.3% (95% confidence interval [CI], 81.6%-92.1%). Across seven studies (n = 283 patients), the pooled 6-month mortality was 5.4% (95% CI, 1.4%-11.2%). An individual patient data analysis of three studies (n = 282 patients) yielded a primary patency rate of 95.2% (95% CI, 92.7%-97.8%), 82.8% (95% CI, 78.3%-87.6%), 79.8% (95% CI, 75.0%-85.0%), and 79.8% (95% CI, 75.0%-85.0%) at 6, 12, 18, and 24 months, respectively. The 12-month target lesion revascularization rate across four studies (n = 324 patients) was 9.6% (95% CI, 6.4%-13.4%). In the two-stage meta-analysis of 6-month primary patency across three studies (n = 168 patients), the use of SESs was significantly favored over BMSs (risk ratio, 1.28; 95% CI, 1.12-1.46; P < .001). CONCLUSIONS: The overall evidence suggests that the use of SESs appears to be safe and offers favorable outcomes for BTK arterial disease compared with BMSs.

The ARRIVE guidelines 2.0: Updated guidelines for reporting animal research.

Reproducible science requires transparent reporting. The ARRIVE guidelines (Animal Research: Reporting of In Vivo Experiments) were originally developed in 2010 to improve the reporting of animal research. They consist of a checklist of information to include in publications describing in vivo experiments to enable others to scrutinise the work adequately, evaluate its methodological rigour, and reproduce the methods and results. Despite considerable levels of endorsement by funders and journals over the years, adherence to the guidelines has been inconsistent, and the anticipated improvements in the quality of reporting in animal research publications have not been achieved. Here, we introduce ARRIVE 2.0. The guidelines have been updated and information reorganised to facilitate their use in practice. We used a Delphi exercise to prioritise and divide the items of the guidelines into 2 sets, the "ARRIVE Essential 10," which constitutes the minimum requirement, and the "Recommended Set," which describes the research context. This division facilitates improved reporting of animal research by supporting a stepwise approach to implementation. This helps journal editors and reviewers verify that the most important items are being reported in manuscripts. We have also developed the accompanying Explanation and Elaboration (E&E) document, which serves (1) to explain the rationale behind each item in the guidelines, (2) to clarify key concepts, and (3) to provide illustrative examples. We aim, through these changes, to help ensure that researchers, reviewers, and journal editors are better equipped to improve the rigour and transparency of the scientific process and thus reproducibility.

Reporting animal research: Explanation and elaboration for the ARRIVE guidelines 2.0.

Improving the reproducibility of biomedical research is a major challenge. Transparent and accurate reporting is vital to this process; it allows readers to assess the reliability of the findings and repeat or build upon the work of other researchers. The ARRIVE guidelines (Animal Research: Reporting In Vivo Experiments) were developed in 2010 to help authors and journals identify the minimum information necessary to report in publications describing in vivo experiments. Despite widespread endorsement by the scientific community, the impact of ARRIVE on the transparency of reporting in animal research publications has been limited. We have revised the ARRIVE guidelines to update them and facilitate their use in practice. The revised guidelines are published alongside this paper. This explanation and elaboration document was developed as part of the revision. It provides further information about each of the 21 items in ARRIVE 2.0, including the rationale and supporting evidence for their inclusion in the guidelines, elaboration of details to report, and examples of good reporting from the published literature. This document also covers advice and best practice in the design and conduct of animal studies to support researchers in improving standards from the start of the experimental design process through to publication.

Symptoms and associated impact in pre- and postmenopausal women with sexual arousal disorder: a concept elicitation study.

BACKGROUND: Approximately 26% of adult women in the United States suffer from female sexual arousal disorder (FSAD), yet little has been done to compare the experience of FSAD in pre- and postmenopausal women, which is critical to enhance the current understanding of FSAD and inform the development and assessment of treatment options for these patient populations. AIM: To explore the experience of condition-associated symptoms and the relative importance of FSAD symptoms, including their severity, bother, and impact, on participants' health-related quality of life (HRQoL) in pre- and postmenopausal women with FSAD. METHODS: In-depth, qualitative, semistructured concept elicitation interviews were conducted with premenopausal (n = 23) and postmenopausal (n = 13) women who were clinically diagnosed with FSAD by a trained sexual medicine clinician. All interviews were audio recorded and transcribed verbatim by a professional transcription company. Thematic analysis was performed with the assistance of NVivo qualitative analysis software. OUTCOMES: Outcomes included qualitative interview data about FSAD symptoms and HRQoL, as well as a comparison between pre- and postmenopausal populations. RESULTS: The most frequently reported symptom in both cohorts was "inability or difficulty with orgasm" (premenopausal, n = 21; postmenopausal, n = 13). The symptom that premenopausal women most desired to have treated was lubrication, and for postmenopausal women, it was a lack of lubrication or wetness and loss of feeling/sensation. In total, 21 of 23 premenopausal women and all 13 postmenopausal women reported a lack of feeling or sensation in the genitals. The most frequently reported HRQoL impact in both groups was decreased confidence. CLINICAL IMPLICATIONS: Results from this study suggest that the manifestation and experience of FSAD are similar in pre- and postmenopausal women and that the unmet need for an FSAD treatment in the postmenopausal population is just as great as that of the premenopausal population. STRENGTHS AND LIMITATIONS: This study involved in-depth qualitative interviews with a relatively small group of women (N = 36) recruited from only 5 study sites across the United States. CONCLUSION: The analysis of qualitative data from the concept elicitation interviews revealed a substantial physical and emotional burden of FSAD, underscoring the need for Food and Drug Administration-approved treatment options for pre- and postmenopausal women with FSAD.

Inhibition of colony stimulating factor-1 receptor (CSF-1R) as a potential therapeutic strategy for neurodegenerative diseases: opportunities and challenges.

Microglia are specialized dynamic immune cells in the central nervous system (CNS) that plays a crucial role in brain homeostasis and in disease states. Persistent neuroinflammation is considered a hallmark of many neurodegenerative diseases, including Alzheimer's disease (AD), Parkinson's disease (PD), Huntington's disease (HD), amyotrophic lateral sclerosis (ALS) and primary progressive multiple sclerosis (MS). Colony stimulating factor 1-receptor (CSF-1R) is predominantly expressed on microglia and its expression is significantly increased in neurodegenerative diseases. Cumulative findings have indicated that CSF-1R inhibitors can have beneficial effects in preclinical neurodegenerative disease models. Research using CSF-1R inhibitors has now been extended into non-human primates and humans. This review article summarizes the most recent advances using CSF-1R inhibitors in different neurodegenerative conditions including AD, PD, HD, ALS and MS. Potential challenges for translating these findings into clinical practice are presented.