Arginine-linked HPV-associated E7 displaying bacteria-derived outer membrane vesicles as a potent antigen-specific cancer vaccine.

BACKGROUND: Bacteria-based cancer therapy have demonstrated innovative strategies to combat tumors. Recent studies have focused on gram-negative bacterial outer membrane vesicles (OMVs) as a novel cancer immunotherapy strategy due to its intrinsic properties as a versatile carrier. METHOD: Here, we developed an Human Papillomavirus (HPV)-associated E7 antigen displaying Salmonella-derived OMV vaccine, utilizing a Poly(L-arginine) cell penetrating peptide (CPP) to enhance HPV16 E7 (aa49-67) H-2 Db and OMV affinity, termed SOMV-9RE7. RESULTS: Due to OMV's intrinsic immunogenic properties, SOMV-9RE7 effectively activates adaptive immunity through antigen-presenting cell uptake and antigen cross-presentation. Vaccination of engineered OMVs shows immediate tumor suppression and recruitment of infiltrating tumor-reactive immune cells. CONCLUSION: The simplicity of the arginine coating strategy boasts the versatility of immuno-stimulating OMVs that can be broadly implemented to personalized bacterial immunotherapeutic applications.

FLT3L-induced virtual memory CD8 T cells engage the immune system against tumors.

BACKGROUND: Previous research in FMS-like tyrosine kinase 3 ligands (FLT3L) has primarily focused on their potential to generate dendritic cells (DCs) from bone marrow progenitors, with a limited understanding of how these cells affect CD8 T cell function. In this study, we further investigated the in vivo role of FLT3L for the immunomodulatory capabilities of CD8 T cells. METHODS: Albumin-conjugated FLT3L (Alb-FLT3L) was generated and applied for translational medicine purposes; here it was used to treat naïve C57BL/6 and OT1 mice for CD8 T cell response analysis. Syngeneic B16ova and E.G7ova mouse models were employed for adoptive cell transfer to evaluate the effects of Alb-FLT3L preconditioning of CD8 T cells on tumor progression. To uncover the underlying mechanisms of Alb-FLT3L modulation, we conducted bulk RNA-seq analysis of the CD44high CD8 T cells. STAT1-deficient mice were used to elucidate the functional roles of Alb-FLT3L in the modulation of T cells. Finally, antibody blockade of type one interferon signaling and in vitro coculture of plasmacytoid DCs (pDCs) with naive CD8 T cells was performed to determine the role of pDCs in mediating regulation of CD44high CD8 T cells. RESULTS: CD44high CD8 T cells were enhanced in C57BL/6 mice administrated with Alb-FLT3L. These CD8 T cells exhibited virtual memory features and had greater proliferative and effective functions. Notably, the adoptive transfer of CD44high naïve CD8 T cells into C57BL/6 mice with B16ova tumors led to significant tumor regression. RNA-seq analysis of the CD44high naïve CD8 T cells revealed FLT3L to induce CD44high CD8 T cells in a JAK-STAT1 signaling pathway-dependent manner, as supported by results indicating a decreased ability of FLT3L to enhance CD8 T cell proliferation in STAT1-deficient mice as compared to wild-type control mice. Moreover, antibody blockade of type one interferon signaling restricted the generation of FLT3L-induced CD44high CD8 T cells, while CD44 expression was able to be induced in naïve CD8 T cells cocultured with pDCs derived from FLT3L-treated mice. This suggests the crucial role of pDCs in mediating FLT3L regulation of CD44high CD8 T cells. CONCLUSIONS: These findings provide critical insight and support the therapeutic potential of Alb-FLT3L as an immune modulator in preconditioning of naïve CD8 T cells for cancer immunotherapy.

Referrals to Community and State Agencies to Address Social Determinants of Health for Improving Mental Health, Functioning, and Quality of Care Outcomes for Diverse Adults.

Objectives. To examine whether referral for social determinants of health (SDH) needs decreases psychological distress and posttraumatic stress disorder (PTSD) symptoms and improves level of functioning and quality of care among diverse adults. Methods. Data are from control participants (n = 503 adults) in a randomized controlled trial testing a mental health intervention in North Carolina and Massachusetts. We fitted multilevel mixed-effects models to repeated assessments (baseline, 3, 6, and 12 months) collected between September 2019 and January 2023. Results. After referral to services for trouble paying utility bills, participants reported lower PTSD symptoms. Participants reported better quality of care when receiving referrals to mental health care. After adjusting for income and employment status, we found that participants who were referred more often also had lower PTSD symptoms and better levels of functioning. Conclusions. Referrals for certain SDH needs might decrease PTSD symptoms and improve self-reported quality of care and functioning. However, referrals alone, without ensuring receipt of services, might be insufficient to affect other mental health outcomes. Research is needed on training and providing care managers time for offering interpersonal support, securing services, and understanding agencies' contexts for addressing high SDH needs. (Am J Public Health. 2024;114(S3):S278-S288. https://doi.org/10.2105/AJPH.2023.307442).

Effects of online care on functional and psychological outcomes in patients with psoriasis: A randomized controlled trial.

BACKGROUND: The impact of online care on patients' functional and psychological outcomes is critical to determine yet still unknown. OBJECTIVE: To evaluate how a novel online health model that facilitates physician-patient collaboration compares with in-person care for improving functional status and mental health of patients with psoriasis. METHODS: This 12-month randomized controlled equivalency trial randomly assigned patients with psoriasis 1:1 to receive online or in-person care. Functional impairment and depression were assessed at baseline and at 3-month intervals using the 5-level EuroQol-5 Dimensions index and Patient Health Questionnare-9. RESULTS: Overall, 296 patients were randomly assigned to the online or in-person groups. The between-group difference in overall improvement in the EuroQol Visual Analogue Scale was -0.002 (95% confidence interval, -2.749 to 2.745), falling within an equivalence margin of ±8. The between-group difference in overall improvement in the 5-level EuroQol-5 Dimensions index was 0 (95% confidence interval, -0.003 to 0.003), falling within an equivalence margin of ±0.1. The between-group difference in overall improvement in Patient Health Questionnare-9 score was -0.33 (95% CI, -1.20 to 0.55), falling within an equivalence margin of ±3. LIMITATIONS: Slightly different attrition rates between online and in-person arms (11% vs 9%), but no impact on outcomes. CONCLUSION: The online health model was equivalent to in-person care for reducing functional impairment and depressive symptoms in patients with psoriasis.

Unique Subtype of Microglia in Degenerative Thalamus After Cortical Stroke.

BACKGROUND AND PURPOSE: Stroke disrupts neuronal functions in both local and remotely connected regions, leading to network-wide deficits that can hinder recovery. The thalamus is particularly affected, with progressive development of neurodegeneration accompanied by inflammatory responses. However, the complexity of the involved inflammatory responses is poorly understood. Herein we investigated the spatiotemporal changes in the secondary degenerative thalamus after cortical stroke, using targeted transcriptome approach in conjunction with histology and flow cytometry. METHODS: Cortical ischemic stroke was generated by permanent occlusion of the left middle cerebral artery in male C57BL6J mice. Neurodegeneration, neuroinflammatory responses, and microglial activation were examined in naive and stroke mice at from poststroke days (PD) 1 to 84, in both ipsilesional somatosensory cortex and ipsilesional thalamus. NanoString neuropathology panel (780 genes) was used to examine transcriptome changes at PD7 and PD28. Fluorescence activated cell sorting was used to collect CD11c+ microglia from ipsilesional thalamus, and gene expressions were validated by quantitative real-time polymerase chain reaction. RESULTS: Neurodegeneration in the thalamus was detected at PD7 and progressively worsened by PD28. This was accompanied by rapid microglial activation detected as early as PD1, which preceded the neurodegenerative changes. Transcriptome analysis showed higher number of differentially expressed genes in ipsilesional thalamus at PD28. Notably, neuroinflammation was the top activated pathway, and microglia was the most enriched cell type. Itgax (CD11c) was the most significantly increased gene, and its expression was highly detected in microglia. Flow-sorted CD11c+ microglia from degenerative thalamus indicated molecular signatures similar to neurodegenerative disease-associated microglia; these included downregulated Tmem119 and CX3CR1 and upregulated ApoE, Axl, LpL, CSF1, and Cst7. CONCLUSIONS: Our findings demonstrate the dynamic changes of microglia after stroke and highlight the importance of investigating stroke network-wide deficits. Importantly, we report the existence of a unique subtype of microglia (CD11c+) with neurodegenerative disease-associated microglia features in the degenerative thalamus after stroke.

A review and roadmap of the skin, lung and gut microbiota in systemic sclerosis.

As our understanding of the genetic underpinnings of SSc increases, questions regarding the environmental trigger(s) that induce and propagate SSc in the genetically predisposed individual emerge. The interplay between the environment, the immune system, and the microbial species that inhabit the patient's skin and gastrointestinal tract is a pathobiological frontier that is largely unexplored in SSc. The purpose of this review is to provide an overview of the methodologies, experimental study results and future roadmap for elucidating the relationship between the SSc host and his/her microbiome.

Contrasting lexical biases in bilingual English-Mandarin speech: Verb-biased mothers, but noun-biased toddlers.

Is noun dominance in early lexical acquisition a widespread or a language-specific phenomenon? Thirty Singaporean bilingual English-Mandarin learning toddlers and their mothers were observed in a mother-child play interaction. For both English and Mandarin, toddlers' speech and reported vocabulary contained more nouns than verbs across book reading and toy playing. In contrast, their mothers' speech contained more verbs than nouns in both English and Mandarin but differed depending on the context of the interaction. Although toddlers demonstrated a noun bias for both languages, the noun bias was more pronounced in English than in Mandarin. Together, these findings support early noun dominance as a widespread phenomenon in the lexical acquisition debate but also provide evidence that language specificity also plays a minor role in children's early lexical development.

Successful Management of Anti-TNF-Induced Psoriasis Despite Continuation of Therapy in a Pyoderma Gangrenosum Patient

Pyoderma gangrenosum is an inflammatory, neutrophil-mediated disorder that is difficult to treat. Tumor necrosis factor and other inflammatory mediators are among the most promising therapeutic targets. We present a case of a 60-year-old woman with recalcitrant pyoderma gangrenosum treated with adalimumab, who paradoxically developed psoriasis. Secukinumab, an interleukin-17 inhibitor, was added to her regimen, resulting in successful treatment of her psoriasis. Secukinumab was later replaced by methotrexate, resulting in remission of both pyoderma gangrenosum and maintenance of a psoriasis-free state. We conclude that paradoxically induced psoriatic lesions can resolve with adjunct therapy despite continuation of anti-tumor necrosis factor agents. J Drugs Dermatol. 2020;19(2)199-201. doi:10.36849/JDD.2020.4662

The development and testing of a nurse-led smartphone-based self-management programme for diabetes patients with poor glycaemic control.

AIMS: To describe a systematic process for the development of a nurse-led smartphone-based self-management programme for type 2 diabetes patients with poor glycaemic control in Singapore. METHODS: A three-step process involving the application of a theoretical framework, evidence from literature, content validity, and pilot tests were conducted for the content and technical development of the programme. Content experts and lay patients evaluated the appropriateness, relevance, and comprehensibility of the newly developed Care4Diabetes application. A pilot randomized controlled trial was conducted with 40 patients recruited in Singapore. Twenty patients each were randomly allocated to the control and intervention groups. The study outcomes were collected at baseline and at 3 months thereafter. RESULTS: The nurse-led smartphone-based self-management programme was developed with integration of the Care4Diabetes application and the web-portal system. The pilot results indicated that the effects of this smartphone-based programme on patient's health-related outcomes were comparable with those of the currently available nurse-led diabetes service. CONCLUSION: The smartphone-based self-management intervention was deemed effective, yet full-scale randomized controlled trials are still ongoing and the results of these may provide strong evidence of the effectiveness of such an approach in improving patient care. IMPACT: The uniqueness of this study lies in the integrated system used, which offers a clinical platform for diabetes nurses to provide personalized coaching and care to patients remotely, while monitoring patients' progress closely. By adopting such an approach, it would free up more time for nurses to cater to patients who are more critically in need of their direct attention.

Nurses' perception and experiences towards medical device-related pressure injuries: A qualitative study.

AIMS AND OBJECTIVES: This study aims to explore nurses' perceptions and experiences regarding pressure injuries caused by medical devices and to understand the perceived challenges and barriers nurses face in preventing medical device-related pressure injuries. BACKGROUND: Nurses have a responsibility to prevent pressure injuries and play a major role in their prevention. As there has been a lack of research on medical device-related pressure injuries, not much is known about nurses' perceptions and experiences. This therefore hinders the establishment of effective and efficient interventions in nurses' education and in the practical environment. DESIGN: A descriptive qualitative design was adopted, and the COREQ checklist was employed to report on the current study. METHODS: The study was conducted at an acute care hospital in Singapore. Purposive sampling was used, and a total of 21 enrolled and registered nurses who had recent experiences with medical device-related pressure injuries were recruited between August and December 2018. Face-to-face interviews were conducted using a semi-structured interview guide. A thematic analysis was performed to analyse the qualitative data. RESULTS: Five themes emerged regarding pressure injuries: (1) preventable yet unavoidable, (2) everyone's responsibility, (3) harmonising theory with practice reality, (4) pre-existing conditions may limit injury prevention and management; and (5) nurses expressed a need for experiential training. CONCLUSIONS: The study's findings could be used to develop improvements in nursing practice and policy at acute care hospitals, as well as to improve awareness of medical device-related pressure injuries among healthcare professionals. Moreover, the findings can also inform future research studies to develop effective evidence-based practices and improve patient outcomes. RELEVANCE TO THE CLINICAL PRACTICE: This study reveals the unique challenges and dilemmas that nurses face and will help to inform healthcare institutions and management in developing programmes and improving protocols to reduce the incidence rate of pressure injuries caused by medical device.

Consensus Paper: Experimental Neurostimulation of the Cerebellum.

The cerebellum is best known for its role in controlling motor behaviors. However, recent work supports the view that it also influences non-motor behaviors. The contribution of the cerebellum towards different brain functions is underscored by its involvement in a diverse and increasing number of neurological and neuropsychiatric conditions including ataxia, dystonia, essential tremor, Parkinson's disease (PD), epilepsy, stroke, multiple sclerosis, autism spectrum disorders, dyslexia, attention deficit hyperactivity disorder (ADHD), and schizophrenia. Although there are no cures for these conditions, cerebellar stimulation is quickly gaining attention for symptomatic alleviation, as cerebellar circuitry has arisen as a promising target for invasive and non-invasive neuromodulation. This consensus paper brings together experts from the fields of neurophysiology, neurology, and neurosurgery to discuss recent efforts in using the cerebellum as a therapeutic intervention. We report on the most advanced techniques for manipulating cerebellar circuits in humans and animal models and define key hurdles and questions for moving forward.

Clinical Relevance of Home Monitoring of Vital Signs and Blood Glucose Levels: A Narrative Review.

OBJECTIVES: We sought to assess the presence and reporting quality of peer-reviewed literature concerning the accuracy, precision, and reliability of home monitoring technologies for vital signs and glucose determinations in older adult populations. METHODS: A narrative literature review was undertaken searching the databases Medline, Embase, and Compendex. Peer-reviewed publications with keywords related to vital signs, monitoring devices and technologies, independent living, and older adults were searched. Publications between the years 2012 and 2018 were included. Two reviewers independently conducted title and abstract screening, and four reviewers independently undertook full-text screening and data extraction with all disagreements resolved through discussion and consensus. RESULTS: Two hundred nine articles were included. Our review showed limited assessment and low-quality reporting of evidence concerning the accuracy, precision, and reliability of home monitoring technologies. Of 209 articles describing a relevant device, only 45 percent (n = 95) provided a citation or some evidence to support their validation claim. Of forty-eight articles that described the use of a comparator device, 65 percent (n = 31) used low-quality statistical methods, 23 percent (n = 11) used moderate-quality statistical methods, and only 12 percent (n = 6) used high-quality statistical methods. CONCLUSIONS: Our review found that current validity claims were based on low-quality assessments that do not provide the necessary confidence needed by clinicians for medical decision-making purposes. This narrative review highlights the need for standardized health technology reporting to increase health practitioner confidence in these devices, support the appropriate adoption of such devices within the healthcare system, and improve health outcomes.

Eosinophilic fasciitis presenting as a unilateral, solitary plaque.

Eosinophilic fasciitis is a rare connective tissue disorder characterized by inflammation of the fascia that leads to painful, indurated skin. Because of its variable clinical presentation and overlap with conditions, such as morphea, the diagnosis of eosinophilic fasciitis can be challenging and relies on clinical presentation, histopathologic and laboratory analysis, and response to therapy. Herein, we present an unusual, solitary, isolated plaque with pathologic features and response to therapy most consistent with eosinophilic fasciitis.

End stage scurvy in the developed world: A diagnostic conundrum but not to be mistaken for pyoderma gangrenosum.

Scurvy is a clinical syndrome, resulting from ascorbic acid deficiency. Prevalence of the condition is now extremely low in the Western population and its diagnosis can be challenging without a high index of suspicion. When cases do present, they are often misdiagnosed initially. Therefore, a thorough history, physical exam, and laboratory evaluation are key to showing this now rare but extremely well-known disease. We report a case of scurvy manifesting as persistent non-healing lower-extremity ulcerations, initially mistaken for pyoderma gangrenosum. The patient responded to appropriate replacement therapy, but ulcers were slow to heal. As was the case in our patient, symptom reversal may require additional nutritional replacement. We encourage physicians to consider nutritional deficiencies in their differential diagnoses and highlight the incidence of malnutrition in the proper clinical setting to avoid diagnostic delay.

RNA-Sequencing Analysis Revealed a Distinct Motor Cortex Transcriptome in Spontaneously Recovered Mice After Stroke.

Background and Purpose- Many restorative therapies have been used to study brain repair after stroke. These therapeutic-induced changes have revealed important insights on brain repair and recovery mechanisms; however, the intrinsic changes that occur in spontaneously recovery after stroke is less clear. The goal of this study is to elucidate the intrinsic changes in spontaneous recovery after stroke, by directly investigating the transcriptome of primary motor cortex in mice that naturally recovered after stroke. Methods- Male C57BL/6J mice were subjected to transient middle cerebral artery occlusion. Functional recovery was evaluated using the horizontal rotating beam test. A novel in-depth lesion mapping analysis was used to evaluate infarct size and locations. Ipsilesional and contralesional primary motor cortices (iM1 and cM1) were processed for RNA-sequencing transcriptome analysis. Results- Cluster analysis of the stroke mice behavior performance revealed 2 distinct recovery groups: a spontaneously recovered and a nonrecovered group. Both groups showed similar lesion profile, despite their differential recovery outcome. RNA-sequencing transcriptome analysis revealed distinct biological pathways in the spontaneously recovered stroke mice, in both iM1 and cM1. Correlation analysis revealed that 38 genes in the iM1 were significantly correlated with improved recovery, whereas 74 genes were correlated in the cM1. In particular, ingenuity pathway analysis highlighted the involvement of cAMP signaling in the cM1, with selective reduction of Adora2a (adenosine receptor A2A), Drd2 (dopamine receptor D2), and Pde10a (phosphodiesterase 10A) expression in recovered mice. Interestingly, the expressions of these genes in cM1 were negatively correlated with behavioral recovery. Conclusions- Our RNA-sequencing data revealed a panel of recovery-related genes in the motor cortex of spontaneously recovered stroke mice and highlighted the involvement of contralesional cortex in spontaneous recovery, particularly Adora2a, Drd2, and Pde10a-mediated cAMP signaling pathway. Developing drugs targeting these candidates after stroke may provide beneficial recovery outcome.

Successful Treatment of Severe Alopecia Areata With Oral or Topical Tofacitinib.

Alopecia areata is an autoimmune disease involving the hair follicle with a chronic, relapsing course. Tofacitinib is Janus kinase inhibitor approved for treatment of rheumatoid arthritis that has been shown to be effective in treatment of alopecia areata. We present a case series of 11 patients with severe alopecia areata on longstanding, regular to high dose oral tofacitinib with marked hair regrowth. Additionally, we present a case of moderate to severe alopecia areata successfully treated with topical tofacitinib cream. J Drugs Dermatol. 2018;17(7):800-803.

Circulating cathelicidin levels correlate with mucosal disease activity in ulcerative colitis, risk of intestinal stricture in Crohn's disease, and clinical prognosis in inflammatory bowel disease.

BACKGROUND: Cathelicidin (LL-37) is an antimicrobial peptide known to be associated with various autoimmune diseases. We attempt to determine if cathelicidin can accurately reflect IBD disease activity. We hypothesize that serum cathelicidin correlates with mucosal disease activity, stricture, and clinical prognosis of IBD patients. METHODS: Serum samples were collected from two separate cohorts of patients at the University of California, Los Angeles. Cohort 1 consisted of 50 control, 23 UC, and 28 CD patients. Cohort 2 consisted of 20 control, 57 UC, and 67 CD patients. LL-37 levels were determined by ELISA. Data from both cohorts were combined for calculation of accuracies in indicating mucosal disease activity, relative risks of stricture, and odds ratios of predicting disease development. RESULTS: Serum cathelicidin levels were inversely correlated with Partial Mayo Scores of UC patients and Harvey-Bradshaw Indices of CD patients. Among IBD patients with moderate or severe initial disease activity, the patients with high initial LL-37 levels had significantly better recovery than the patients with low initial LL-37 levels after 6-18 months, suggesting that high LL-37 levels correlate with good prognosis. Co-evaluation of LL-37 and CRP levels was more accurate than CRP alone or LL-37 alone in the correlation with Mayo Endoscopic Score of UC patients. Low LL-37 levels indicated a significantly elevated risk of intestinal stricture in CD patients. CONCLUSION: Co-evaluation of LL-37 and CRP can indicate mucosal disease activity in UC patients. LL-37 can predict future clinical activity in IBD patients and indicate risk of intestinal stricture in CD patients.

Phellinus species: An emerging cause of refractory fungal infections in patients with X-linked chronic granulomatous disease.

Aspergillus spp. are a leading cause of mortality in chronic granulomatous disease (CGD), but other fungi have emerged in the era of mould prophylaxis. Of these, Phellinus spp. are an under-recognised cause of invasive fungal infections (IFIs) in CGD, and data on their presentation and management are scarce. We present a patient with CGD who developed disseminated IFI involving the lungs and brain. Surgical specimens grew a basidiomycete which was disregarded as a contaminant. After three months of progressive disease despite antifungals, he was diagnosed with Phellinus tropicalis by internal transcribed spacer (ITS) sequencing. He improved with amphotericin B and isavuconazole but required haematopoietic stem cell transplantation (HSCT). We review the literature on Phellinus infections in CGD and conclude that: (i) these infections emerge on mould-active prophylaxis and are indolent; (ii) they typically cause locally destructive disease but can disseminate; (iii) diagnosis is delayed and requires molecular methods; (iv) amphotericin B is most active in vitro; and (v) treatment is protracted and requires surgery and possibly HSCT. In conclusion, Phellinus spp. are emerging pathogens in CGD. Every effort should be made to establish the diagnosis of non-Aspergillus IFIs in patients with CGD by sending tissue specimens for molecular diagnostics.

Optogenetic neuronal stimulation promotes functional recovery after stroke.

Clinical and research efforts have focused on promoting functional recovery after stroke. Brain stimulation strategies are particularly promising because they allow direct manipulation of the target area's excitability. However, elucidating the cell type and mechanisms mediating recovery has been difficult because existing stimulation techniques nonspecifically target all cell types near the stimulated site. To circumvent these barriers, we used optogenetics to selectively activate neurons that express channelrhodopsin 2 and demonstrated that selective neuronal stimulations in the ipsilesional primary motor cortex (iM1) can promote functional recovery. Stroke mice that received repeated neuronal stimulations exhibited significant improvement in cerebral blood flow and the neurovascular coupling response, as well as increased expression of activity-dependent neurotrophins in the contralesional cortex, including brain-derived neurotrophic factor, nerve growth factor, and neurotrophin 3. Western analysis also indicated that stimulated mice exhibited a significant increase in the expression of a plasticity marker growth-associated protein 43. Moreover, iM1 neuronal stimulations promoted functional recovery, as stimulated stroke mice showed faster weight gain and performed significantly better in sensory-motor behavior tests. Interestingly, stimulations in normal nonstroke mice did not alter motor behavior or neurotrophin expression, suggesting that the prorecovery effect of selective neuronal stimulations is dependent on the poststroke environment. These results demonstrate that stimulation of neurons in the stroke hemisphere is sufficient to promote recovery.