Transcriptome analysis of rheumatoid arthritis uncovers genes linked to inflammation-induced pain.

Autoimmune diseases such as rheumatoid arthritis (RA) can promote states of chronic inflammation with accompanying tissue destruction and pain. RA can cause inflammatory synovitis in peripheral joints, particularly within the hands and feet, but can also sometimes trigger temporomandibular joint (TMJ) arthralgia. To better understand the effects of ongoing inflammation-induced pain signaling, dorsal root ganglia (DRGs) were acquired from individuals with RA for transcriptomic study. We conducted RNA sequencing from the L5 DRGs because it contains the soma of the sensory neurons that innervate the affected joints in the foot. DRGs from 5 RA patients were compared with 9 non-arthritic controls. RNA-seq of L5 DRGs identified 128 differentially expressed genes (DEGs) that were dysregulated in the RA subjects as compared to the non-arthritic controls. The DRG resides outside the blood brain barrier and, as such, our initial transcriptome analysis detected signs of an autoimmune disorder including the upregulated expression of immunoglobulins and other immunologically related genes within the DRGs of the RA donors. Additionally, we saw the upregulation in genes implicated in neurogenesis that could promote pain hypersensitivity. Overall, our DRG analysis suggests that there are upregulated inflammatory and pain signaling pathways that can contribute to chronic pain in RA.

Impact of clinically unsuspected venous thrombotic events on CVC removal and survival in pediatric cancer patients: A population-based study from the Maritimes, Canada.

Venous thromboembolism (VTE) is a well-recognized complication in pediatric cancer patients. We aimed to determine the frequency of central venous catheter (CVC) removal and survival impact of children with cancer who develop VTE. After ethics approval, a retrospective population-based study of cancer patients less than 21 years between 2005 and 2020, in the Maritime Provinces Nova Scotia, New Brunswick, and Prince Edward Island was conducted. Clinical data was collected from hospital charts and online medical records. Data on demographics, cancer diagnosis and treatment, diagnosis of VTE, use of CVC, were assessed. Kaplan-Meier survival curves were computed and compared among study groups. This study included 770 patients with a male to female ratio of 1.1:1. There were 49 patients with symptomatic VTE, 49 patients with clinically unsuspected VTE, and 671 patients with no VTE. There were 15 (1.9%) non-CVC-symptomatic (ncsVTE), 34 (4.4%) CVC-symptomatic (csVTE), 40 (5.2%) non-CVC-clinically unsuspected (ncuVTE), 9 (1.2%) CVC-clinically unsuspected (cVTE), and 671 (87%) no VTE patients. The mean number of CVCs required during treatment was significantly higher among patients with VTE (p < 0.001). Both symptomatic and clinically unsuspected VTE required significantly more CVCs compared to no VTE patients (p < 0.001 and p = 0.049 respectively). Kaplan-Meier survival curves showed ncsVTE patients' survival was significantly reduced compared to all other patients (p < 0.001). This study demonstrates that pediatric oncology patients with ncsVTE have significantly lower survival. This suggests that ncsVTE may be a biomarker for increased disease burden. This study also demonstrated that clinically unsuspected VTE had significantly more CVCs placed during treatment compared to patients without a VTE, indicating the need for better screening.

Origin and maintenance of large ribosomal RNA gene repeat size in mammals.

The genes encoding ribosomal RNA are highly conserved across life and in almost all eukaryotes are present in large tandem repeat arrays called the rDNA. rDNA repeat unit size is conserved across most eukaryotes but has expanded dramatically in mammals, principally through the expansion of the intergenic spacer region that separates adjacent rRNA coding regions. Here, we used long-read sequence data from representatives of the major amniote lineages to determine where in amniote evolution rDNA unit size increased. We find that amniote rDNA unit sizes fall into two narrow size classes: "normal" (∼11-20 kb) in all amniotes except monotreme, marsupial, and eutherian mammals, which have "large" (∼35-45 kb) sizes. We confirm that increases in intergenic spacer length explain much of this mammalian size increase. However, in stark contrast to the uniformity of mammalian rDNA unit size, mammalian intergenic spacers differ greatly in sequence. These results suggest a large increase in intergenic spacer size occurred in a mammalian ancestor and has been maintained despite substantial sequence changes over the course of mammalian evolution. This points to a previously unrecognized constraint on the length of the intergenic spacer, a region that was thought to be largely neutral. We finish by speculating on possible causes of this constraint.

The impact of biomarkers of malignancy (IMWG SLiM criteria) in myeloma in a real-world population: Clinical characteristics, therapy and outcomes from the Australian and New Zealand Myeloma and Related Diseases Registry (ANZ MRDR).

A decade after International Myeloma Working Group (IMWG) biomarkers (SLiM criteria) were introduced, this real-world study examined their impact on diagnosis, therapy and outcomes in myeloma. Using the ANZ MRDR, 3489 newly diagnosed patients from 2013 to 2023, comprising 3232 diagnosed by CRAB ('CRAB patients', including 1758 who also satisfied ≥1 SLiM criteria) and 257 by SLiM ('SLiM patients') criteria were analysed. CRAB patients had higher R-ISS and lower performance status, with no difference in cytogenetic risk. SLiM patients had improved progression-free survival (PFS, 37.5 vs. 32.2 months, hazard ratio [HR] 1.31 [1.08-1.59], p = 0.003), overall survival (80.9 vs. 73.2 months, HR 1.64 [1.26-2.13], p < 0.001) and PFS2 (54.6 vs. 40.3 months, HR 1.51 [1.22-1.86], p < 0.001) compared with CRAB patients, partially explained by earlier diagnosis, with no differential impact between the plasma cell and light-chain criteria on PFS. However, 34% of CRAB patients did not manifest SLiM characteristics, raising the possibility that SLiM features are associated with different biological behaviours contributing to a better prognosis, for example, improved PFS2 in SLiM patients suggested less disease resistance at first relapse. These data support earlier initiation of therapy by SLiM. The superior survival outcomes of SLiM versus CRAB patients highlight the importance of defining these subgroups when interpreting therapeutic outcomes at induction and first relapse.

Transcriptome Analysis of Rheumatoid Arthritis Uncovers Genes Linked to Inflammation-Induced Pain.

Autoimmune diseases such as rheumatoid arthritis (RA) can promote states of chronic Inflammation with accompanying tissue destruction and pain. RA can cause inflammatory synovitis in peripheral joints, particularly within the hands and feet, but can also sometimes trigger temporomandibular joint (TMJ) arthralgia. To better understand the effects of ongoing Inflammation-induced pain signaling, dorsal root ganglia (DRGs) were acquired from individuals with RA for transcriptomic study. We conducted RNA sequencing from the L5 DRGs because it contains the soma of the sensory neurons that innervate the affected joints in the foot. DRGs from 5 RA patients were compared with 9 non-arthritic controls. RNA-seq of L5 DRGs identified 128 differentially expressed genes (DEGs) that were dysregulated in the RA subjects as compared to the non-arthritic controls. The DRG resides outside the blood brain barrier and, as such, our initial transcriptome analysis detected signs of an autoimmune disorder including the upregulated expression of immunoglobulins and other immunologically related genes within the DRGs of the RA donors. Additionally, we saw the upregulation in genes implicated in neurogenesis that could promote pain hypersensitivity. overall, our DRG analysis suggests that there are upregulated inflammatory and pain signaling pathways that can contribute to chronic pain in RA.

Dissociable encoding of motivated behavior by parallel thalamo-striatal projections.

The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process relies on motivational states that are guided by internal drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)1,2,3,4,5,6,7,8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem.3,9,10,11,12,13,14 Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc.4,15,16 In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a foraging-like behavioral task. We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) neurons also mirrored some of these parameters, but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

Bacterial heat shock protein genes during induction chemotherapy in pediatric patients with acute lymphoblastic leukemia.

Background: Heat shock proteins (HSP) protect cancer cells. Gastrointestinal bacteria contain HSP genes and can release extracellular vesicles which act as biological shuttles. Stress from treatment may result in a microbial community with more HSP genes, which could contribute to circulating HSP levels. Methods: The authors examined the abundance of five bacterial HSP genes pre-treatment and during induction in stool sequences from 30 pediatric acute lymphoblastic leukemia patients. Results: Decreased mean HTPG counts (p = 0.0024) pre-treatment versus induction were observed. During induction, HTPG, Shannon diversity and Bacteroidetes decreased (p = 7.5e-4; 1.1e-3; 8.6e-4), while DNAK and Firmicutes increased (p = 6.9e-3; 9.2e-4). Conclusion: Understanding microbial HSP gene community changes with treatment is the first step in determining if bacterial HSPs are important to the tumor microenvironment and leukemia treatment.

Dissociable encoding of motivated behavior by parallel thalamo-striatal projections.

The successful pursuit of goals requires the coordinated execution and termination of actions that lead to positive outcomes. This process is thought to rely on motivational states that are guided by internal drivers, such as hunger or fear. However, the mechanisms by which the brain tracks motivational states to shape instrumental actions are not fully understood. The paraventricular nucleus of the thalamus (PVT) is a midline thalamic nucleus that shapes motivated behaviors via its projections to the nucleus accumbens (NAc)1-8 and monitors internal state via interoceptive inputs from the hypothalamus and brainstem3,9-14. Recent studies indicate that the PVT can be subdivided into two major neuronal subpopulations, namely PVTD2(+) and PVTD2(-), which differ in genetic identity, functionality, and anatomical connectivity to other brain regions, including the NAc4,15,16. In this study, we used fiber photometry to investigate the in vivo dynamics of these two distinct PVT neuronal types in mice performing a reward foraging-like behavioral task. We discovered that PVTD2(+) and PVTD2(-) neurons encode the execution and termination of goal-oriented actions, respectively. Furthermore, activity in the PVTD2(+) neuronal population mirrored motivation parameters such as vigor and satiety. Similarly, PVTD2(-) neurons, also mirrored some of these parameters but to a much lesser extent. Importantly, these features were largely preserved when activity in PVT projections to the NAc was selectively assessed. Collectively, our results highlight the existence of two parallel thalamo-striatal projections that participate in the dynamic regulation of goal pursuits and provide insight into the mechanisms by which the brain tracks motivational states to shape instrumental actions.

The long-distance relationship between Dirofilaria and the UK: case report and literature review.

Over the last two decades, vector-borne pathogens (VBPs) have changed their distribution across the globe as a consequence of a variety of environmental, socioeconomic and geopolitical factors. Dirofilaria immitis and Dirofilaria repens are perfect exemplars of European VBPs of One Health concern that have undergone profound changes in their distribution, with new hotspots of infection appearing in previously non-endemic countries. Some areas, such as the United Kingdom, are still considered non-endemic. However, a combination of climate change and the potential spread of invasive mosquito species may change this scenario, exposing the country to the risk of outbreaks of filarial infections. Only a limited number of non-autochthonous cases have been recorded in the United Kingdom to date. These infections remain a diagnostic challenge for clinicians unfamiliar with these "exotic" parasites, which in turn complicates the approach to treatment and management. Therefore, this review aims to (i) describe the first case of D. repens infection in a dog currently resident in Scotland, (ii) summarise the available literature on Dirofilaria spp. infections in both humans and animals in the United Kingdom and (iii) assess the suitability of the United Kingdom for the establishment of these new VBPs.

Literacy and self-rated health: Analysis of the Longitudinal and International Study of Adults (LISA).

The relationship between education and health is well-established. The empirical literature finds that individuals with higher levels of education experience lower risks of poor health outcomes compared to individuals with less education. Outstanding to this literature is the examination of a dimension of education - literacy - and its association with health. The objective of this study was to examine the relationship between literacy (reading, numeracy) and health (self-reported health). We use data from the 2012 wave of the Canadian Longitudinal International Survey of Adults (LISA). The LISA includes rich information on health, broader sociodemographic characteristics (income, age, sex, etc.) as well as information on literacy skills from the Program for International Assessment of Adult Competencies (PIAAC). Using logistic regression, we first reaffirm the association between education and self-reported health. We then find that after controlling for measures of literacy, understood as proficiency in reading and numeracy, the magnitude of effect of education on health is reduced. Skills in literacy reduce the risk of reporting poor health, but only for the older subset of respondents (ages 40-65). Our results suggest that literacy should not be understated in empirical research on education and health, and in fact serve to sharpen our understanding of how education impacts health by drawing attention to indirect pathways.

Transcriptomic analysis of human sensory neurons in painful diabetic neuropathy reveals inflammation and neuronal loss.

Pathological sensations caused by peripheral painful neuropathy occurring in Type 2 diabetes mellitus (T2DM) are often described as 'sharp' and 'burning' and are commonly spontaneous in origin. Proposed etiologies implicate dysfunction of nociceptive sensory neurons in dorsal root ganglia (DRG) induced by generation of reactive oxygen species, microvascular defects, and ongoing axonal degeneration and regeneration. To investigate the molecular mechanisms contributing to diabetic pain, DRGs were acquired postmortem from patients who had been experiencing painful diabetic peripheral neuropathy (DPN) and subjected to transcriptome analyses to identify genes contributing to pathological processes and neuropathic pain. DPN occurs in distal extremities resulting in the characteristic "glove and stocking" pattern. Accordingly, the L4 and L5 DRGs, which contain the perikarya of primary afferent neurons innervating the foot, were analyzed from five DPN patients and compared with seven controls. Transcriptome analyses identified 844 differentially expressed genes. We observed increases in levels of inflammation-associated transcripts from macrophages in DPN patients that may contribute to pain hypersensitivity and, conversely, there were frequent decreases in neuronally-related genes. The elevated inflammatory gene profile and the accompanying downregulation of multiple neuronal genes provide new insights into intraganglionic pathology and mechanisms causing neuropathic pain in DPN patients with T2DM.

Podiatrist-Delivered Health Coaching to Facilitate the Use of a Smart Insole to Support Foot Health Monitoring in People with Diabetes-Related Peripheral Neuropathy.

This trial evaluated the feasibility of podiatrist-led health coaching (HC) to facilitate smart-insole adoption and foot monitoring in adults with diabetes-related neuropathy. Adults aged 69.9 ± 5.6 years with diabetes for 13.7 ± 10.3 years participated in this 4-week explanatory sequential mixed-methods intervention. An HC training package was delivered to podiatrists, who used HC to issue a smart insole to support foot monitoring. Insole usage data monitored adoption. Changes in participant understanding of neuropathy, foot care behaviours, and intention to adopt the smart insole were measured. Focus group and in-depth interviews explored quantitative data. Initial HC appointments took a mean of 43.8 ± 8.8 min. HC fidelity was strong for empathy/rapport and knowledge provision but weak for assessing motivational elements. Mean smart-insole wear was 12.53 ± 3.46 h/day with 71.2 ± 13.9% alerts not effectively off-loaded, with no significant effect for time on usage F(3,6) = 1.194 (p = 0.389) or alert responses F(3,6) = 0.272 (p = 0.843). Improvements in post-trial questionnaire mean scores and focus group responses indicate podiatrist-led HC improved participants' understanding of neuropathy and implementation of footcare practices. Podiatrist-led HC is feasible, supporting smart-insole adoption and foot monitoring as evidenced by wear time, and improvements in self-reported footcare practices. However, podiatrists require additional feedback to better consolidate some unfamiliar health coaching skills. ACTRN12618002053202.

Detection of SARS-CoV-2 in respiratory samples from cats in the UK associated with human-to-cat transmission.

OBJECTIVES: The aim of the study was to find evidence of SARS-CoV-2 infection in UK cats. DESIGN: Tissue samples were tested for SARS-CoV-2 antigen using immunofluorescence and for viral RNA by in situ hybridisation. A set of 387 oropharyngeal swabs that had been submitted for routine respiratory pathogen testing was tested for SARS-CoV-2 RNA using reverse transcriptase quantitative PCR. RESULTS: Lung tissue collected post-mortem from cat 1 tested positive for both SARS-CoV-2 nucleocapsid antigen and RNA. SARS-CoV-2 RNA was detected in an oropharyngeal swab collected from cat 2 that presented with rhinitis and conjunctivitis. High throughput sequencing of the viral genome revealed five single nucleotide polymorphisms (SNPs) compared to the nearest UK human SARS-CoV-2 sequence, and this human virus contained eight SNPs compared to the original Wuhan-Hu-1 reference sequence. An analysis of the viral genome of cat 2 together with nine other feline-derived SARS-CoV-2 sequences from around the world revealed no shared cat-specific mutations. CONCLUSIONS: These findings indicate that human-to-cat transmission of SARS-CoV-2 occurred during the COVID-19 pandemic in the UK, with the infected cats developing mild or severe respiratory disease. Given the ability of the new coronavirus to infect different species, it will be important to monitor for human-to-cat, cat-to-cat and cat-to-human transmission.

Factors influencing Australian podiatrists' behavioural intentions to adopt a smart insole into clinical practice: a mixed methods study.

BACKGROUND: Diabetes is the leading cause of lower limb amputation in Australia, costing the Australian health care system an estimated A$1.6 billion annually. Podiatrists are the primary foot health care provider in Australia. Research suggests that health professional attitudes can impact patient utilisation of e-health technologies, such as wearable foot monitoring devices aimed at preventing foot ulceration. The aim of this study was to explore factors that impact the intentions of Australian podiatrists to adopt smart insole foot monitoring technology. METHODS: A mixed methods explanatory sequential design was undertaken. One hundred and eleven Australian podiatrists completed an online version of the validated Unified Theory of Acceptance and Use of Technology (UTAUT) questionnaire. Multiple regression analysis was used to determine the strongest predictive model of podiatrists' behavioural intention to adopt technology. Additionally, two focus groups were conducted, and thematic analysis was performed to explore podiatrists' perceived barriers and enablers to smart insole adoption. RESULTS: One hundred and eleven Australian podiatrists completed the online UTAUT questionnaire. The majority of respondents practiced in the private sector (58.6%) and were female (50.5%), with Victoria the most common practice location (39.6%). Significant positive correlations existed between behavioural intention and six psychosocial domains including performance expectancy (r = 0.64, p < 0.001), effort expectancy (r = 0.47, p < 0.001), attitude (r = 0.55, p < 0.001), social influence (r = 0.45, p < 0.001), facilitating conditions (r = 0.36, p < 0.001), and self-efficacy (r = 0.30, p < 0.002). Multiple regression analysis determined that performance expectancy alone was most predictive of behavioural intention to adopt a smart insole into clinical practice (adjusted R2 = 42%, p < 0.001). Qualitative analyses revealed that podiatrists believed that the insole would increase patient knowledge, engagement and self-efficacy. However, concerns were raised about cost, footwear issues and the device's utility with elderly and remote populations. CONCLUSIONS: Performance expectancy was the most important psychosocial factor predicting the intentions of Australian podiatrists to adopt smart insole foot monitoring technologies. While Australian podiatrists are open to adopting smart insoles into clinical practice, evidence of the device's efficacy is a precursor to adoption. Other perceived barriers to adoption including device cost, compatibility with off-loading, footwear issues and patient age also need to be addressed prior to implementation and clinical adoption.

Investigating the therapeutic potential of cognitive bias modification for high anxiety sensitivity.

BACKGROUND AND OBJECTIVES: Individuals with high anxiety sensitivity (AS) display negative interpretive biases in response to uncomfortable but nondangerous physical sensations. Research suggests that modifying interpretation biases associated with AS leads to changes in AS. The present study sought to replicate and extend this research by addressing limitations of previous studies, increasing the amount of training and adding a follow-up period. METHOD: Participants high in AS were randomly assigned to four sessions of computerized interpretation bias modification (CBM-I) training or four sessions of computerized "sham" training (control condition) over a 2-week period. The outcomes were AS, interpretive biases, and reactions to induced physical sensations. Assessments occurred at baseline, during training, immediately after the final training session, and 2 weeks after the final training; number of re-assessments varied by outcome. RESULTS: The CBM-I condition did not outperform the control condition. At the end of the training period, the CBM-I condition displayed limited reductions in AS and interpretation biases. There were no changes in reactions to induced physical sensations. Similar results were found in the control condition for all outcomes. LIMITATIONS: The control task and the dose of training may have obscured potential effects of CBM-I. CONCLUSIONS: When considered within the context of previous research, the experimental effects and therapeutic potential of CBM-I for high AS appear to be minimal. However, methodological questions need to be resolved before such a conclusion can be considered definitive.

Role of the nurse in identifying and addressing health inequalities.

This article aims to improve nurses' knowledge and understanding of health inequalities. Health inequalities are responsible for variation in health outcomes observed across different population groups. Therefore, it is essential that nurses have an understanding of the health inequalities that can occur, and their causes. This knowledge will enable nurses to address the challenges that health inequalities can create in nursing practice. This article raises awareness of this important aspect of care, so that nurses can successfully identify and address the health inequalities that they encounter in their practice, thus enabling a holistic approach to patient care.

Factors influencing behavioural intention to use a smart shoe insole in regionally based adults with diabetes: a mixed methods study.

BACKGROUND: Smart insole technologies that provide biofeedback on foot health can support foot-care in adults with diabetes. However, the factors that influence patient uptake and acceptance of this technology are unclear. Therefore, the aim of this mixed-methods study was to use an established theoretical framework to determine a model of psychosocial factors that best predicts participant intention to use smart insoles. METHODS: Fifty-three adults with diabetes from regional Australia completed the validated Unified Theory of Acceptance and Use of Technology (UTAUT) questionnaire. Multiple regression analysis was used to determine the psychosocial factors that best predict behavioural intention to adopt a smart insole. Additionally, a focus group was conducted and thematic analysis was performed to explore barriers and enablers to adopting this technology. RESULTS: The multiple regression model that best predicted intention to adopt the smart insole (adjusted R2 = 0.51, p < 0.001) identified that self-efficacy (ß = 0.67, p = 0.001) and attitude (ß = 0.72, p < 0.001) were significant predictors of behavioural intention, while effort expectancy (ß = - 0.52, p = 0.003) and performance expectancy (ß = - 0.40, p = 0.040) were moderating factors. Thematic analysis illustrates the importance of attitude and self-efficacy on participants' behavioural intentions, influenced by participant's belief in the device's clinical efficacy and anticipated effort expectancy. CONCLUSIONS: This mixed-methods study demonstrates that attitude, self-efficacy, performance expectancy and effort expectancy combine to predict intention to adopt smart insole technology. Clinicians should consider these psychosocial factors when they prescribe and implement smart soles with patients at high risk of foot ulceration.

Randomized in situ clinical trial evaluating erosion protection efficacy of a 0.454% stannous fluoride dentifrice.

OBJECTIVES: To assess the protective effects of a 0.454% stabilized stannous fluoride dentifrice and a marketed triclosan dentifrice against enamel erosion in a 10-day in situ model. METHODS: This was a double-blind, randomized, 2-treatment, 4-period, crossover in situ trial involving healthy adult participants. Participants were randomized to a treatment sequence involving the following products: a highly bioavailable 0.454% stannous fluoride dentifrice (Procter & Gamble) and a marketed dentifrice control containing 0.24% sodium fluoride and 0.3% triclosan (Colgate-Palmolive). Each study period took place over 10 days. Participants wore an intra-oral appliance retaining two polished human enamel samples for 6 hours per day. Two times per day they swished with the assigned dentifrice slurry and four times per day they swished with 250 mL of orange juice (25 mL per minute) over a 10-minute period. Contact profilometry measurements were made for each sample at baseline and day 10 to determine surface change. RESULTS: Thirty-six participants were enrolled and 33 completed the study (mean age = 40.5 years). The stannous fluoride dentifrice demonstrated 93.5% less enamel loss than the NaF/triclosan dentifrice (P < 0.001) at Day 10, with median enamel loss of 0.097 µm and 1.495 µm, respectively. Both products were well tolerated. CONCLUSION: The stannous fluoride dentifrice demonstrated significantly greater erosion protection efficacy relative to the NaF/triclosan dentifrice in this randomized in situ clinical trial.

Hippocampal-Evoked Feedforward Inhibition in the Nucleus Accumbens.

The nucleus accumbens (NAc) is critical for motivated behavior and is rewired following exposure to drugs of abuse. Medium spiny neurons (MSNs) in the NAc express either D1 or D2 receptors and project to distinct downstream targets. Differential activation of these MSNs depends on both excitation from long-range inputs and inhibition via the local circuit. Assessing how long-range excitatory inputs engage inhibitory circuitry is therefore important for understanding NAc function. Here, we use slice electrophysiology and optogenetics to study ventral hippocampal (vHPC)-evoked feedforward inhibition in the NAc of male and female mice. We find that vHPC-evoked excitation is stronger at D1+ than D1- MSNs, whereas inhibition is unbiased at the two cell types. vHPC inputs contact both parvalbumin-positive (PV+) and somatostatin-positive (SOM+) interneurons, but PV+ cells are preferentially activated. Moreover, suppressing PV+ interneurons indicates they are primarily responsible for vHPC-evoked inhibition. Finally, repeated cocaine exposure alters the excitation of D1+ and D1- MSNs, without concomitant changes to inhibition, shifting the excitation/inhibition balance. Together, our results highlight the contributions of multiple interneuron populations to feedforward inhibition in the NAc. Moreover, they demonstrate that inhibition provides a stable backdrop on which drug-evoked changes to excitation occur within this circuit.SIGNIFICANCE STATEMENT Given the importance of the nucleus accumbens (NAc) in reward learning and drug-seeking behaviors, it is critical to understand what controls the activity of cells in this region. While excitatory inputs to projection neurons in the NAc have been identified, it is unclear how the local inhibitory network becomes engaged. Here, we identify a sparse population of interneurons responsible for feedforward inhibition evoked by ventral hippocampal input and characterize their connections within the NAc. We also demonstrate that the balance of excitation and inhibition that projection neurons experience is altered by exposure to cocaine. Together, this work provides insight into the fundamental circuitry of this region as well as the effects of drugs of abuse.