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.

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.

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.

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.

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.

Balancing the Demands of Two Tasks: An Investigation of Cognitive-Motor Dual-Tasking in Relapsing Remitting Multiple Sclerosis.

BACKGROUND: People with relapsing remitting multiple sclerosis (PwRRMS) suffer disproportionate decrements in gait under dual-task conditions, when walking and a cognitive task are combined. There has been much less investigation of the impact of cognitive demands on balance. OBJECTIVES: This study investigated whether: (1) PwRRMS show disproportionate decrements in postural stability under dual-task conditions compared to healthy controls, and (2) dual-task decrements are associated with everyday dual-tasking difficulties. The impact of mood, fatigue, and disease severity on dual-tasking was also examined. METHODS: A total of 34 PwRRMS and 34 matched controls completed cognitive (digit span) and balance (movement of center of pressure on Biosway on stable and unstable surfaces) tasks under single- and dual-task conditions. Everyday dual-tasking was measured using the Dual-Tasking Questionnaire. Mood was measured by the Hospital Anxiety & Depression Scale. Fatigue was measured via the Modified Fatigue Index Scale. RESULTS: No differences in age, gender, years of education, estimated pre-morbid IQ, or baseline digit span between groups. Compared with controls, PwRRMS showed significantly greater decrement in postural stability under dual-task conditions on an unstable surface (p=.007), but not a stable surface (p=.679). Balance decrement scores were not correlated with everyday dual-tasking difficulties or fatigue. Stable surface balance decrement scores were significantly associated with levels of anxiety (rho=0.527; p=.001) and depression (rho=0.451; p=.007). CONCLUSIONS: RRMS causes dual-tasking difficulties, impacting balance under challenging conditions, which may contribute to increased risk of gait difficulties and falls. The relationship between anxiety/depression and dual-task decrement suggests that emotional factors may be contributing to dual-task difficulties. (JINS, 2018, 24, 247-258).

Randomized clinical trial to determine if changes in dentin tubule occlusion visualized by SEM of replica impressions correlate with pain scores.

PURPOSE: To quantify dentin tubule occlusion and correlate this with pain reduction in vivo. METHODS: This was a single-center, randomized two treatment, examiner-blind, parallel study. 20 participants with confirmed dentin hypersensitivity (DH) were evaluated by Schiff Air Blast, VAS Air Blast and replica impression of the tooth surface to visualize tubule occlusion at baseline and following 4-week twice daily use of either an occluding toothpaste (8% strontium acetate, 1,040 ppm fluoride) or a non-occluding toothpaste (1,450 ppm fluoride). RESULTS: Both treatments increased tubule occlusion significantly from baseline to 4 weeks (P= 0.01) with significant decreases in pain score only seen with the occluding toothpaste (Schiff, P= 0.01; VAS, P= 0.01). Schiff pain score after 4 weeks was markedly reduced following treatment with the occluding toothpaste as compared to the non-occluding toothpaste, (P= 0.05) with no significant differences between the pastes for occlusion score or patient reported VAS, although the scores favored the occluding toothpaste. CLINICAL SIGNIFICANCE: Occlusion scores as obtained by replica impression techniques with SEM imaging correlate significantly with DH pain scores confirming proof of concept. With further refinement, this technique could be used to accurately quantify tubule occlusion in vivo and the associated pain reduction achieved by occluding toothpastes.

Erosion protection efficacy of a 0.454% stannous fluoride dentifrice versus an arginine-containing dentifrice.

PURPOSE: To assess the anti-erosion effects of a 0.454% stannous fluoride dentifrice versus a marketed dentifrice in an in situ clinical study. METHODS: This was a double-blind, randomized and controlled, two-treatment, four-period crossover clinical study involving healthy adults. Each study period was 10 days. Subjects were randomized to one of two dentifrice products each period: an experimental 0.454% stannous fluoride dentifrice (1,100 ppm fluoride) or a marketed 1.5% arginine-containing dentifrice (Colgate Maximum Cavity Protection, 1,450 ppm fluoride). Subjects wore an intra-oral appliance fitted with two polished human enamel samples for 6 hours per day, swishing with the assigned dentifrice slurry twice a day in addition to sipping and swishing with 250 ml of orange juice for 10 minutes (in increments of 25 ml each minute) four times each day. Contact profilometry was used to measure surface loss of tooth enamel over the course of the study. Two measurements for each sample were taken at baseline and Day 10. RESULTS: 35 subjects were randomized to treatment and 31 completed the study (mean age = 40 years). At Day 10, enamel loss means were 0.128 µm for the stannous fluoride dentifrice and 1.377 µm for the arginine-containing dentifrice, respectively (P< 0.001). This represents 90.7% less enamel loss for the stannous fluoride dentifrice. Both products were well tolerated. CLINICAL SIGNIFICANCE: The 0.454% stannous fluoride dentifrice demonstrated significantly greater protection to human enamel against erosive acid challenges relative to the marketed 1.5% arginine-containing dentifrice in this in situ clinical study.

An examination of distress intolerance in undergraduate students high in symptoms of generalized anxiety disorder.

People with generalized anxiety disorder (GAD) engage in maladaptive coping strategies to reduce or avoid distress. Evidence suggests that uncertainty and negative emotions are triggers for distress in people with GAD; however, there may also be other triggers. Recent conceptualizations have highlighted six types of experiences that people report having difficulty withstanding: uncertainty, negative emotions, ambiguity, frustration, physical discomfort, and the perceived consequences of anxious arousal. The present study examined the extent to which individuals high in symptoms of GAD are intolerant of these distress triggers, compared to individuals high in depressive symptoms, and individuals who are low in GAD and depressive symptoms. Undergraduate students (N = 217) completed self-report measures of GAD symptoms, depressive symptoms, and distress intolerance. Individuals high in GAD symptoms reported greater intolerance of all of the distress triggers compared to people low in symptoms of GAD and depression. Individuals high in GAD symptoms reported greater intolerance of physical discomfort compared to those high in depressive symptoms. Furthermore, intolerance of physical discomfort was the best unique correlate of GAD status, suggesting that it may be specific to GAD (versus depression). These findings support continued investigation of the transdiagnosticity and specificity of distress intolerance.

A randomised in situ trial, measuring the anti-erosive properties of a stannous-containing sodium fluoride dentifrice compared with a sodium fluoride/potassium nitrate dentifrice.

OBJECTIVES: To determine if a stabilised, stannous-containing sodium fluoride dentifrice provides greater enamel protection in situ against intraoral dietary erosive challenges compared with a sodium fluoride/potassium nitrate dentifrice. METHODS: A single-centre, investigator blind, randomised, supervised, two-treatment, non-brushing, four-period crossover in situ study was undertaken, with each test period being 15 days. Thirty-five healthy adult subjects were recruited to participate in the study, which included four erosive acid challenges per day. Subjects were randomised to product treatment, which included either: (1) a stannous-containing sodium fluoride dentifrice (Oral-B(®) Pro-Expert Sensitive) or (2) a sodium fluoride/potassium nitrate dentifrice (Sensodyne(®) Pronamel(®) ). Each study subject wore an intraoral appliance retaining two sterilised, polished human enamel samples for 6 hours/day. Subjects swished with an allocated dentifrice slurry twice a day and with 250 ml of orange juice for 10 minutes (25 ml/minute over a 10-minute period) four times per day. The primary and secondary outcomes for this study were enamel loss measured using contact profilometry at days 15 and 5, respectively, using parametric analysis methods. RESULTS: At day 15, a 38% lower enamel loss (P < 0.0001) was observed, with estimated medians of 2.03 µm (SE 0.247) and 3.30 µm (SE 0.379), in favour of the stannous-containing dentifrice. At day 5, specimens treated with the stannous-containing sodium fluoride dentifrice demonstrated 25% less enamel loss than those treated with the sodium fluoride/potassium nitrate dentifrice. Treatment differences at day 5 were also statistically significant (P < 0.05), with estimated medians of 1.37 µm (SE 0.177) and 1.83 µm (SE 0.223), respectively. CONCLUSIONS: Results of this in situ study suggest the stabilised, stannous-containing sodium fluoride dentifrice could be used to provide significantly greater protection to enamel from erosive acid challenge compared with that provided by conventional fluoride-containing products.

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.

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.

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.

Evaluation of stain removal and inhibition properties of eight denture cleansers: an in vitro study.

OBJECTIVES: To determine the ability of eight denture cleansers to remove and inhibit tea-stain build-up on acrylic resin. MATERIALS AND METHODS: In the stain removal study, Perspex(®) (cast heat polymerised resin) specimens previously soaked in saliva were stained using multiple exposures of chlorhexidine and tea solutions. Specimens were exposed for 1 min to one of the eight denture cleansers for five cycles, washed and dried and their optical density read on a uv/vis spectrophotometer at 295 nm. In the stain inhibition study, clear specimens were exposed to saliva followed by cleansers then tea solution, for five cycles. The build-up of stain at each cycle was measured, and differences in optical densities from baseline were calculated. RESULTS: All denture cleansers were significantly more effective than water in removing stain (p < 0.05). There were significant differences in cleaning ability between cleansers (p < 0.001), Dentural(®) and Kleenite(®) were particularly effective. The stain inhibition experiment showed that most cleansers were significantly more effective than water in inhibiting stain (p < 0.05). There were significant differences in inhibition ability between cleansers (p < 0.01). Kleenite(®) and Equate were particularly effective. CONCLUSIONS: All denture cleansers had a capacity to remove stain and most had an inhibitory effect on staining. Kleenite(®) was particularly effective in controlling stain formation.

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.

A randomised crossover trial to compare the potential of stannous fluoride and essential oil mouth rinses to induce tooth and tongue staining.

This study compared the staining potential of two experimental amine fluoride/stannous fluoride mouth rinses (A and B), a phenolic/essential oil rinse (C) and a negative control, water, rinse (D). The study was a single centre, randomized, single-blind, four treatment crossover study design among healthy participants. Prior to each study period, participants received a dental prophylaxis. On the Monday of each period, subjects suspended oral hygiene, and under supervision, rinsed with the allocated mouth rinse immediately followed by a warm black tea solution at hourly intervals eight times a day for 4 days. On Friday, the area and intensity of staining on the teeth, the primary outcome measure and dorsum of tongue were assessed. This regimen was repeated for all the three subsequent treatment periods. Rinse B produced less stain than rinse A, but the difference was not significant (p = 0.20). Rinse B produced significantly more stain than rinse C (p < 0.05) and D (p < 0.001). For tongue staining, rinse B produced significantly more staining than D (p < 0.01) but not A or C. Overall, all test rinses produced more staining than placebo with an overall pattern for more staining with stannous formulations. Individuals using stannous or phenolic/essential oil mouth rinse formulations should be advised of the possible staining side effect and that this can be easily removed by a professional dental cleaning.

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.

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.