Next-generation 3D printed multipurpose prevention intravaginal ring for prevention of HIV, HSV-2, and unintended pregnancy.

Globally, nearly half of all pregnancies are unintended, ~1.3 million new human immunodeficiency virus (HIV) infections are reported every year, and more than 500 million people are estimated to have a genital herpes simplex virus (HSV-2) infection. Here we report the first 3D printed multipurpose prevention technology (MPT) intravaginal ring (IVR) for prevention of HIV, HSV-2, and unintended pregnancy. The IVRs were fabricated using state-of-the-art Continuous Liquid Interface Production (CLIP™) 3D printing technology using a biocompatible silicone-urethane based resin. Anti-HIV drug (Dapivirine, DPV), anti-herpes drug (Pritelivir, PTV) and a contraceptive drug (Levonorgestrel, LNG) were loaded in a macaque size IVR (25 mm outer diameter, OD; 6.0 mm cross-section, CS) allometrically scaled from the human size (54 mm OD; 7.6 mm CS) IVR analogue. All three active pharmaceutical ingredients (APIs) were loaded in the IVR using a single-step drug loading process driven by absorption. DPV, PTV, and LNG elicited zero-order release kinetics in vitro in simulated vaginal fluid (SVF) at pH 4 and pH 8 relevant to human and macaque vaginal pH respectively. CLIP 3D printed MPT IVRs remained stable after 6 months of storage at 4 °C with no change in physical, dimensional, or mechanical properties and no change in drug concentration and absence of drug degradation byproducts. The MPT IVRs elicited sustained release of all three APIs in macaques for 28 days with median plasma concentrations of 138 pg/mL (DPV), 18,700 pg/mL (PTV), and 335 pg/mL (LNG). Safety studies demonstrated that the MPT IVRs were safe and well tolerated in the macaques with no observed change or abnormalities in vaginal pH and no significant changes in any of the 22 mucosal cytokines and chemokines tested including pro-inflammatory (IL-1ß, IL-6, IL-8, IFN-γ, TNF-α, IL-17, IL-18) and anti-inflammatory (IL-10, IL-12) cytokines while the MPT IVR was in place or after its removal. Additionally, MPT IVRs elicited no observed alterations in systemic CD4+ and CD8+ T cells during the entire study. Collectively, the proposed MPT IVR has potential to expand preventative choices for young women and girls against unintended pregnancy against two highly prevalent sexually transmitted infections (STIs).

Alzheimer's disease-associated protective variant Plcg2-P522R modulates peripheral macrophage function in a sex-dimorphic manner.

Genome-wide association studies have identified a protective mutation in the phospholipase C gamma 2 (PLCG2) gene which confers protection against Alzheimer's disease (AD)-associated cognitive decline. Therefore, PLCG2, which is primarily expressed in immune cells, has become a target of interest for potential therapeutic intervention. The protective allele, known as P522R, has been shown to be hyper-morphic in microglia, increasing phagocytosis of amyloid-beta (Aß), and increasing the release of inflammatory cytokines. However, the effect of this protective mutation on peripheral tissue-resident macrophages, and the extent to which sex modifies this effect, has yet to be assessed. Herein, we show that peripheral macrophages carrying the P522R mutation do indeed show functional differences compared to their wild-type (WT) counterparts, however, these alterations occur in a sex-dependent manner. In macrophages from females, the P522R mutation increases lysosomal protease activity, cytokine secretion, and gene expression associated with cytokine secretion and apoptosis. In contrast, in macrophages from males, the mutation causes decreased phagocytosis and lysosomal protease activity, modest increases in cytokine secretion, and induction of gene expression associated with negative regulation of the immune response. Taken together, these results suggest that the mutation may be conferring different effects dependent on sex and cell type, and highlight the importance of considering sex as a biological variable when assessing the effects of genetic variants and implications for potential immune system-targeted therapies.

Addressing menopause symptoms in the primary care setting: opportunity to bridge care delivery gaps.

OBJECTIVE: Menopause symptoms affect quality of life and financial well-being but are often unaddressed in primary care clinics. Therefore, we evaluated the extent of menopause symptom documentation in electronic health records (EHRs) by primary health care professionals. METHODS: We retrospectively reviewed adult women who reported moderate or higher vasomotor symptoms on a Mayo Clinic survey conducted from March 1, 2021, through June 30, 2021. We then assessed adequacy of menopause symptom documentation in the EHRs of these women who had primary care visits during the survey period. We reviewed the percentage of documented vasomotor symptoms from May 1, 2019, through May 1, 2021. RESULTS: In the Mayo Clinic Health System-Northwest Wisconsin Region, 229 women self-reported moderate or higher vasomotor symptoms in the Mayo Clinic survey. Although only 23% of these women had vasomotor symptoms listed in the EHR clinical problem lists, 60% of these women had vasomotor symptoms documented in their clinic notes from the primary care visit. Approximately 6% of women reported hormone therapy use for management of menopause symptoms, and nearly 15% reported use of nonhormone prescription therapies for vasomotor symptoms. CONCLUSIONS: A greater proportion of women in our study had EHR documentation of bothersome menopause symptoms than those reported in other studies, but vasomotor symptoms remain generally untreated. We need better methods for identifying midlife women with bothersome menopause symptoms in primary care clinics so that appropriate treatment options, including hormone therapy, can be discussed and offered.

The coronavirus nsp14 exoribonuclease interface with the cofactor nsp10 is essential for efficient virus replication and enzymatic activity.

Coronaviruses (CoVs) encode nonstructural proteins (nsps) 1-16, which assemble to form replication-transcription complexes that function in viral RNA synthesis. All CoVs encode a proofreading 3'-5' exoribonuclease (ExoN) in nsp14 (nsp14-ExoN) that mediates proofreading and high-fidelity replication and is critical for other roles in replication and pathogenesis. The in vitro enzymatic activity of nsp14 ExoN is enhanced in the presence of the cofactor nsp10. We introduced alanine substitutions in nsp14 of murine hepatitis virus (MHV) at the nsp14-10 interface and recovered mutant viruses with a range of impairments in replication and in vitro biochemical exonuclease activity. Two of these substitutions, nsp14 K7A and D8A, had impairments intermediate between WT-MHV nsp14 and the known ExoN(-) D89A/E91A nsp14 catalytic inactivation mutant. All introduced nsp14-10 interface alanine substitutions impaired in vitro exonuclease activity. Passage of the K7A and D8A mutant viruses selected second-site non-synonymous mutations in nsp14 associated with improved mutant virus replication and exonuclease activity. These results confirm the essential role of the nsp14-nsp10 interaction for efficient enzymatic activity and virus replication, identify proximal and long-distance determinants of nsp14-nsp10 interaction, and support targeting the nsp14-10 interface for viral inhibition and attenuation. IMPORTANCE: Coronavirus replication requires assembly of a replication transcription complex composed of nonstructural proteins (nsp), including polymerase, helicase, exonuclease, capping enzymes, and non-enzymatic cofactors. The coronavirus nsp14 exoribonuclease mediates several functions in the viral life cycle including genomic and subgenomic RNA synthesis, RNA recombination, RNA proofreading and high-fidelity replication, and native resistance to many nucleoside analogs. The nsp-14 exonuclease activity in vitro requires the non-enzymatic co-factor nsp10, but the determinants and importance the nsp14-10 interactions during viral replication have not been defined. Here we show that for the coronavirus murine hepatitis virus, nsp14 residues at the nsp14-10 interface are essential for efficient viral replication and in vitro exonuclease activity. These results shed new light on the requirements for protein interactions within the coronavirus replication transcription complex, and they may reveal novel non active-site targets for virus inhibition and attenuation.

Site-Blocking Antisense Oligonucleotides as a Mechanism to Fine-Tune MECP2 Expression.

Rett syndrome (RTT) is a neurodevelopmental disorder caused by loss-of-function mutations in the methyl CpG binding protein 2 (MECP2) gene. Despite its severe phenotype, studies in mouse models suggest that restoring MeCP2 levels can reverse RTT symptomology. Nevertheless, traditional gene therapy approaches are hindered by MECP2's narrow therapeutic window, complicating the safe delivery of viral constructs without overshooting the threshold for toxicity. The 3' untranslated region (3'UTR) plays a key role in gene regulation, where factors like miRNAs bind to pre-mRNA and fine-tune expression. Given that each miRNA's contribution is modest, blocking miRNA binding may represent a potential therapeutic strategy for diseases with high dosage sensitivity, like RTT. Here, we present a series of site-blocking antisense oligonucleotides (sbASOs) designed to outcompete repressive miRNA binding at the MECP2 3'UTR. This strategy aims to increase MECP2 levels in patients with missense or late-truncating mutations, where the hypomorphic nature of the protein can be offset by increased abundance. Our results demonstrate that sbASOs can elevate MECP2 levels in a dose-dependent manner in SH-SY5Y and patient fibroblast cell lines, plateauing at levels projected to be safe. Confirming in vivo functionality, sbASO administration in wild-type mice led to significant MeCP2 upregulation and the emergence of phenotypes associated with MeCP2 overexpression. In a T158M neural stem cell model of RTT, sbASO treatment significantly increased MECP2 expression and levels of the downstream effector protein, brain-derived neurotrophic factor (BDNF). These findings highlight the potential of sbASO-based therapies for MECP2-related disorders and advocate for their continued development.

Pembrolizumab plus Pharmacologic Ascorbate in the Treatment of Leiomyosarcoma.

Introduction: Leiomyosarcoma (LMS) is a malignancy with smooth muscle differentiation. Metastatic LMS is associated with poor prognosis and limited efficacy of systemic treatment. Novel treatment modalities are desperately needed for this entity. Case Presentation: We report the first use of pembrolizumab plus pharmacologic ascorbate in 3 patients with metastatic LMS. All cases resulted in persistent objective responses and disease control significantly better than has been reported with chemotherapy or other immunotherapeutic approaches. Three patients with metastatic LMS, one each of uterine, vascular, and soft tissue origin, were treated with pembrolizumab plus pharmacologic ascorbate. The patient with uterine LMS received combination therapy at presentation and had persistent response for 12 months, which is ongoing. The patient with metastatic LMS of the inferior vena cava received combination therapy at presentation and had persistent response for 12 months, at which time new metastases were found. The patient with soft tissue LMS had disease progression on pembrolizumab monotherapy prior to the addition of ascorbate, after which she had a 17-month response, which is ongoing. No side effects attributed to treatment were reported. Conclusion: Pembrolizumab plus pharmacologic ascorbate is a novel immunotherapeutic approach and warrants further study in LMS.

Obesity and leptin in breast cancer angiogenesis.

At the time of breast cancer diagnosis, most patients meet the diagnostic criteria to be classified as obese or overweight. This can significantly impact patient outcome: breast cancer patients with obesity (body mass index > 30) have a poorer prognosis compared to patients with a lean BMI. Obesity is associated with hyperleptinemia, and leptin is a well-established driver of metastasis in breast cancer. However, the effect of hyperleptinemia on angiogenesis in breast cancer is less well-known. Angiogenesis is an important process in breast cancer because it is essential for tumor growth beyond 1mm3 in size as well as cancer cell circulation and metastasis. This review investigates the role of leptin in regulating angiogenesis, specifically within the context of breast cancer and the associated tumor microenvironment in obese patients.

Thinking outside the brain: Gut microbiome influence on innate immunity within neurodegenerative disease.

The complex network of factors that contribute to neurodegeneration have hampered the discovery of effective preventative measures. While much work has focused on brain-first therapeutics, it is becoming evident that physiological changes outside of the brain are the best target for early interventions. Specifically, myeloid cells, including peripheral macrophages and microglia, are a sensitive population of cells whose activity can directly impact neuronal health. Myeloid cell activity includes cytokine production, migration, debris clearance, and phagocytosis. Environmental measures that can modulate these activities range from toxin exposure to diet. However, one of the most influential mediators of myeloid fitness is the gut microenvironment. Here, we review the current data about the role of myeloid cells in gastrointestinal disorders, Parkinson's disease, dementia, and multiple sclerosis. We then delve into the gut microbiota modulating therapies available and clinical evidence for their use in neurodegeneration. Modulating lifestyle and environmental mediators of inflammation are one of the most promising interventions for neurodegeneration and a systematic and concerted effort to examine these factors in healthy aging is the next frontier.

Spiny mice are primed but fail to regenerate volumetric skeletal muscle loss injuries.

BACKGROUND: In recent years, the African spiny mouse Acomys cahirinus has been shown to regenerate a remarkable array of severe internal and external injuries in the absence of a fibrotic response, including the ability to regenerate full-thickness skin excisions, ear punches, severe kidney injuries, and complete transection of the spinal cord. While skeletal muscle is highly regenerative in adult mammals, Acomys displays superior muscle regeneration properties compared with standard laboratory mice following several injuries, including serial cardiotoxin injections of skeletal muscle and volumetric muscle loss (VML) of the panniculus carnosus muscle following full-thickness excision injuries. VML is an extreme muscle injury defined as the irrecoverable ablation of muscle mass, most commonly resulting from combat injuries or surgical debridement. Barriers to the treatment of VML injury include early and prolonged inflammatory responses that promote fibrotic repair and the loss of structural and mechanical cues that promote muscle regeneration. While the regeneration of the panniculus carnosus in Acomys is impressive, its direct relevance to the study of VML in patients is less clear as this muscle has largely been lost in humans, and, while striated, is not a true skeletal muscle. We therefore sought to test the ability of Acomys to regenerate a skeletal muscle more commonly used in VML injury models. METHODS: We performed two different VML injuries of the Acomys tibialis anterior muscle and compared the regenerative response to a standard laboratory mouse strain, Mus C57BL6/J. RESULTS: Neither Acomys nor Mus recovered lost muscle mass or myofiber number within three months following VML injury, and Acomys also failed to recover force production better than Mus. In contrast, Acomys continued to express eMHC within the injured area even three months following injury, whereas Mus ceased expressing eMHC less than one-month post-injury, suggesting that Acomys muscle was primed, but failed, to regenerate. CONCLUSIONS: While the panniculus carnosus muscle in Acomys regenerates following VML injury in the context of full-thickness skin excision, this regenerative ability does not translate to regenerative repair of a skeletal muscle.

Direct M2 macrophage co-culture overrides viscoelastic hydrogel mechanics to promote fibroblast activation.

Fibroblast activation drives fibrotic diseases such as pulmonary fibrosis. However, the complex interplay of how tissue mechanics and macrophage signals combine to influence fibroblast activation is not well understood. Here, we use hyaluronic acid hydrogels as a tunable cell culture system to mimic lung tissue stiffness and viscoelasticity. We applied this platform to investigate the influence of macrophage signaling on fibroblast activation. Fibroblasts cultured on stiff (50 kPa) hydrogels mimicking fibrotic tissue exhibit increased activation as measured by spreading as well as type I collagen and cadherin-11 expression compared to fibroblasts cultured on soft (1 kPa) viscoelastic hydrogels mimicking normal tissue. These trends were unchanged in fibroblasts cultured with macrophage-conditioned media. However, fibroblasts directly co-cultured with M2 macrophages show increased activation, even on soft viscoelastic hydrogels that normally suppress activation. Inhibition of interleukin 6 (IL6) signaling does not change activation in fibroblast-only cultures but ameliorates the pro-fibrotic effects of M2 macrophage co-culture. These results underscore the ability of direct M2 macrophage co-culture to override hydrogel viscoelasticity to promote fibroblast activation in an IL6-dependent manner. This work also highlights the utility of using hydrogels to deconstruct complex tissue microenvironments to better understand the interplay between microenvironmental mechanical and cellular cues.

Nation-wide surveillance of ticks (Acari: Ixodidae) on birds in Singapore.

Surveillance programs focused on bird ticks are often challenging owing to the difficulty in capturing and screening birds as well as the fact that ticks on avian hosts frequently occur at a low prevalence. Nonetheless, elucidating the diversity and host preferences of avian ticks is critical for understanding public health risks posed by both migratory and resident birds. The first nation-wide surveillance program of avian ticks was initiated to examine bird-tick interactions in Singapore, a key juncture along the East Asian-Australasian flyway. Two tick species were detected, namely Haemaphysalis wellingtoni and Rhipicephalus linnaei, while five bird species were found to host ticks in Singapore, namely Columba livia, Gallus gallus, Ixobrychus flavicollis, Lanius cristatus, and Pitta moluccensis. The threats posed to public health by the human-biting tick H. wellingtoni are discussed along with the potential for migratory birds and ticks to transport tick-borne pathogens into, and through, Singapore.

TLR3 activation mediates partial epithelial-to-mesenchymal transition in human keratinocytes.

TLR3 is expressed in human skin and keratinocytes, and given its varied role in skin inflammation, development, and regeneration, we sought to determine the cellular response in normal human keratinocytes to TLR3 activation. We investigated this mechanism by treating primary human keratinocytes with both UVB, an endogenous and physiologic TLR3 activator, and poly(I:C), a synthetic and selective TLR3 ligand. TLR3 activation with either UVB or poly(I:C) altered keratinocyte morphology, coinciding with the key features of epithelial-to-mesenchymal transition: increased epithelial-to-mesenchymal transition gene expression, enhanced migration, and increased invasion properties. These results confirm and extend previous studies demonstrating that in addition to its classical role in the innate immune response, TLR3 signaling also regulates stem cell-like properties and developmental programs.

Transcriptomic Analyses Predict Enhanced Metabolic Activity and Therapeutic Potential of mTOR Inhibitors in Acne-Prone Skin.

Current acne therapies center on preventing new lesions in patients with acne. These therapies were historically found to be beneficial yet were chosen without knowledge of the specific changes in the skin that favor lesion development. A major challenge in developing new treatments is the incomplete understanding of nonlesional (NL), acne-prone skin's molecular characteristics. To address this, we compared RNA-sequencing data from NL skin of 49 patients with acne (denoted as NL acne [NLA]) with those from 19 healthy controls with no acne history. We found 77 differentially expressed genes in NLA (log fold change > 1; P < .05), including genes associated with innate immunity and epidermal barrier function. Notably, K RT 6C, K RT 16, S100A8, S100A9, and lactotransferrin were upregulated, and LCE4A, LCE6A, and CTSE were downregulated. Gene set enrichment analysis revealed that metabolic pathways were enriched in NLA skin, whereas keratinization was negatively enriched. To identify compounds that could shift the gene expression signature of NLA skin toward healthy control skin, we performed connectivity mapping with the Library of Integrated Network-Based Signatures. We identified 187 compounds, particularly mTOR inhibitors, that could potentially normalize the gene expression profile of acne-prone skin to that of healthy skin. Our findings indicate that NLA skin has distinct differences in epidermal differentiation, cellular metabolism, and innate immunity that may promote lesion formation and suggest that mTOR inhibitors could restore NLA skin toward a healthier state, potentially reversing the predisposition to lesion development.

The Relationship Between Loneliness, Social Isolation, and Inflammatory Bowel Disease: A Narrative Review.

BACKGROUND: There is clear evidence that loneliness and social isolation have profound health consequences. Documenting the associations of loneliness and social isolation with inflammatory bowel disease (IBD) symptoms, disease severity, and treatment outcomes could meaningfully improve health and quality of life in patients with IBD. PURPOSE: The purpose of this narrative review was to synthesize the empirical evidence on the associations of loneliness and social isolation with IBD symptoms, disease severity, and treatment outcomes. METHODS: Articles were identified through systematic database searches. Quantitative studies that enrolled patients with IBD were included if they examined one of the following outcomes: (a) loneliness or social isolation or (b) IBD-related symptoms, disease severity, or treatment outcomes. RESULTS: We identified 1,816 articles after removing duplicates. Of the 18 studies that met the inclusion criteria, 15 were cross-sectional and 3 were longitudinal. Overall, studies found that loneliness was associated with greater disease activity, functional gastrointestinal symptoms, IBD illness stigma, depressive symptoms, daily IBD symptom burden, reduced resilience, and poorer quality of life. Social isolation was associated with higher prevalence of IBD hospitalizations, premature mortality, and depression. CONCLUSIONS: Findings suggest that loneliness and social isolation are associated with poorer health and quality of life in patients with IBD. Prospective cohort studies examining the biobehavioral mechanisms accounting for the associations of loneliness and social isolation with IBD-related outcomes are needed to guide the development of psychological interventions for individuals living with IBD.

This article explores the connection between loneliness, social isolation, and health outcomes in people with inflammatory bowel disease (IBD). While loneliness and social isolation are known to negatively impact health in other chronic diseases, their specific effects within IBD have been far less studied. This study conducted a narrative review and found that loneliness is linked to more severe IBD symptoms, including increased disease activity, greater gastrointestinal distress, and lower quality of life. Similarly, social isolation is associated with higher rates of IBD-related hospitalizations, depression, and reduced coping abilities. These findings highlight the importance of addressing loneliness and social isolation in patients with IBD. Doing so may be key to developing psychological interventions that improve the well-being and health of those living with IBD.

Management of Serious Adverse Events Following Deoxycholic Acid Injection for Submental and Jowl Fat Reduction: A Systematic Review and Management Recommendations.

Pivotal Phase 3 randomized control trials have demonstrated a favorable safety profile for ATX-101 in submental fat (SMF) reduction; however, in real-world settings, several serious adverse events (SAEs) have been reported, most of which are procedure related and avoidable. Current understanding of the management of uncommon AEs and SAEs is based on the aesthetic surgeon's discretion, and overzealous protocols for sclerosis agents are being applied for ATX-101-induced arterial injury. This review focuses on showcasing the management of SAEs reported previously and updating it with personal clinical experiences with ATX-101 for SMF and jowl fat reduction. Along with adherence to the standard procedures for ATX-101 administration, the authors recommend investigating other potential causes of SMF accumulation and jowling mechanism, appropriate demarcation of the surface area to determine the number of vials, and assessment of the fat pad thickness to determine the number of required treatment cycles for optimal therapeutic outcomes. Surgery is preferable for jowling caused by compartment displacement (ptosis), whereas fat-reducing treatments such as ATX-101 are contraindicated for jowling caused by subcutaneous tissue atrophy. Some proactive measures that can be employed to prevent AEs include avoiding intradermal injections to prevent skin ulceration/necrosis, injecting lidocaine to check for smile asymmetry as an indication of marginal mandibular nerve proximity, administering 1 to 2 mm deeper injections in males to prevent alopecia, employing good aseptic techniques to prevent abscess formation, injecting 1 product at a time using correctly labeled syringes, and confirming the diagnosis of pyoderma gangrenosum before treating it as an infection.

Foam Rolling on the Whole Leg and Its Immediate Effects on Postural Control in Collegiate Female Athletes.

The maintenance of body posture relies on mechanoreceptors, suggesting myofascial release could assist postural control. The effects of this have not been well documented, providing room for this investigation. Twenty-one female athletes spent approximately 2.5 minutes foam rolling the calf and thigh muscles on one leg then repeated on opposite leg for a total of 5 minutes. Center of Pressure (CoP) and Limit of Stability (LoS) were assessed using a Bertec posturography plate before (pre-) and after (post-) foam rolling. CoP was measured with eyes open stable surface (EOSS), or eyes closed stable surface (ECSS) and perturbed surface both eyes open (EOPS) and eye closed (ECPS). conditions. LoS was evaluated in the Anterior, Posterior, Left, and Right Directions. A significant effect of Condition for CoP showed ECPS Condition was greatest at both pre- and post-foam rolling (p<0.001). A significant main effect of Direction (p<0.001) showed LoS was greatest in the frontal plane Directions compared to sagittal plane (p<0.01). A significant effect of Time (p<0.05) indicated LoS decreased from Pre- to Post-foam rolling (mean change = 0.569 cm). The study demonstrated that acute effects of self-myofascial release via foam-rolling of the lower extremities can influence postural control.

Osteocyte Sptbn1 Deficiency Alters Cell Survival and Mechanotransduction Following Formation of Plasma Membrane Disruptions (PMD) from Mechanical Loading.

We and others have shown that application of high-level mechanical loading promotes the formation of transient plasma membrane disruptions (PMD) which initiate mechanotransduction. We hypothesized that increasing osteocyte cell membrane fragility, by disrupting the cytoskeleton-associated protein ß2-spectrin (Sptbn1), could alter osteocytic responses and bone adaptation to loading in a PMD-related fashion. In MLO-Y4 cells, treatment with the spectrin-disrupting agent diamide or knockdown of Sptbn1 via siRNA increased the number of PMD formed by fluid shear stress. Primary osteocytes from an osteocyte-targeted DMP1-Cre Sptbn1 conditional knockout (CKO) model mimicked trends seen with diamide and siRNA treatment and suggested the creation of larger PMD, which repaired more slowly, for a given level of stimulus. Post-wounding cell survival was impaired in all three models, and calcium signaling responses from the wounded osteocyte were mildly altered in Sptbn1 CKO cultures. Although Sptbn1 CKO mice did not demonstrate an altered skeletal phenotype as compared to WT littermates under baseline conditions, they showed a blunted increase in cortical thickness when subjected to an osteogenic tibial loading protocol as well as evidence of increased osteocyte death (increased lacunar vacancy) in the loaded limb after 2 weeks of loading. The impaired post-wounding cell viability and impaired bone adaptation seen with Sptbn1 disruption support the existence of an important role for Sptbn1, and PMD formation, in osteocyte mechanotransduction and bone adaptation to mechanical loading.

Peripheral Blood Immune Cells from Individuals with Parkinson's Disease or Inflammatory Bowel Disease Share Deficits in Iron Storage and Transport that are Modulated by Non-Steroidal Anti-Inflammatory Drugs.

Parkinson's Disease (PD) is a multisystem disorder in which dysregulated neuroimmune crosstalk and inflammatory relay via the gut-blood-brain axis have been implicated in PD pathogenesis. Although alterations in circulating inflammatory cytokines and reactive oxygen species (ROS) have been associated with PD, no biomarkers have been identified that predict clinical progression or disease outcome. Gastrointestinal (GI) dysfunction, which involves perturbation of the underlying immune system, is an early and often-overlooked symptom that affects up to 80% of individuals living with PD. Interestingly, 50-70% of individuals with inflammatory bowel disease (IBD), a GI condition that has been epidemiologically linked to PD, display chronic illness-induced anemia - which drives toxic accumulation of iron in the gut. Ferroptotic (or iron loaded) cells have small and dysmorphic mitochondria-suggesting that mitochondrial dysfunction is a consequence of iron accumulation. In pro-inflammatory environments, iron accumulates in immune cells, suggesting a possible connection and/or synergy between iron dysregulation and immune cell dysfunction. Peripheral blood mononuclear cells (PBMCs) recapitulate certain PD-associated neuropathological and inflammatory signatures and can act as communicating messengers in the gut-brain axis. Additionally, this communication can be modulated by several environmental factors; specifically, our data further support existing literature demonstrating a role for non-steroidal anti-inflammatory drugs (NSAIDs) in modulating immune transcriptional states in inflamed individuals. A mechanism linking chronic gut inflammation to iron dysregulation and mitochondrial function within peripheral immune cells has yet to be identified in conferring risk for PD. To that end, we isolated PBMCs and simultaneously evaluated their directed transcriptome and bioenergetic status, to investigate if iron dysregulation and mitochondrial sensitization are linked in individuals living with PD or IBD because of chronic underlying remittent immune activation. We have identified shared features of peripheral inflammation and immunometabolism in individuals living with IBD or PD that may contribute to the epidemiological association reported between IBD and risk for PD.

Systematic Literature Review of the Presentation and Management of Pediatric Relapsing Polychondritis.

INTRODUCTION: Pediatric Relapsing Polychondritis (RP) is a rare autoimmune disorder that causes inflammation and damage to cartilage in children. Common symptoms include pain, swelling and deformities in the ears, nose, trachea, joints, and eyes. The lack of research on the pediatric population necessitates further evaluation of the literature on pediatric RP to summarize existing patterns in presentation, management, and treatment. METHODS: A systematic review was conducted on PubMed and Embase from 1947 to April 2023 on RP in patients under 21 years old abiding by the 2020 PRISMA checklist. Only patient presentations meeting McAdam criteria for RP and including information on management were included. RESULTS: From the 304 initial studies, 54 studies were included for final analysis with a total of 68 patients, who were predominantly female (65%). With a median diagnostic delay of 1 year, the mean age of onset was 12 years old. The most common symptoms on presentation included bilateral auricular chondritis (69%), nasal cartilage inflammation (62%), and respiratory tract chondritis (63%). The most commonly reported information in the literature for the initial workup usually included CT/MRI (72%), bronchoscopy (57%), biopsy (51%), and labs (88%), which most commonly displayed elevated ESR (59%). The most common medications were corticosteroids (91%) and methotrexate (35%) and the most common procedural treatment was tracheostomy (38%). The most efficacious treatment options were monoclonal antibodies (87%, n = 15) and corticosteroids (66%, n = 62) used in 22% and 91% of patients, respectively. The most commonly used monoclonal antibody therapy was infliximab (13%, n = 9). CONCLUSION: The most common presentation for pediatric RP includes chondritis of the ear, nose, and respiratory tract. The most effective treatment options include corticosteroids and monoclonal antibody therapy, such as infliximab. Our findings highlight increasing remission achieved with anti-rheumatic drugs and monoclonal antibody treatment, especially alongside corticosteroids.

Detection and characterization of vector-borne parasites and Wolbachia endosymbionts in greater one-horned rhinoceros (Rhinoceros unicornis) in Nepal.

Vector-borne parasite infections affect both domestic and wild animals. They are often asymptomatic but can result in fatal outcomes under natural and human-induced stressors. Given the limited availability of molecular data on vector-borne parasites in Rhinoceros unicornis (greater one-horned rhinoceros), this study employed molecular tools to detect and characterize the vector-borne parasites in rescued rhinoceros in Chitwan National Park, Nepal. Whole blood samples were collected from thirty-six R. unicornis during rescue and treatment operations. Piroplasmida infections were first screened using nested polymerase chain reaction (PCR) targeting 18S ribosomal RNA gene. Wolbachia was detected by amplifying 16S rRNA gene, while filarial nematodes were detected through amplification of 28S rRNA, COI, myoHC and hsp70 genes. Our results confirmed the presence of Theileria bicornis with a prevalence of 75% (27/36) having two previously unreported haplotypes (H8 and H9). Wolbachia endosymbionts were detected in 25% (9/36) of tested samples and belonged to either supergroup C or F. Filarial nematodes of the genera Mansonella and Onchocerca were also detected. There were no significant association between T. bicornis infections and the age, sex, or location from which the animals were rescued. The high prevalence of Theileria with novel haplotypes along with filarial parasites has important ecological and conservational implications and highlights the need to implement parasite surveillance programs for wildlife in Nepal. Further studies monitoring vector-borne pathogens and interspecies transmission among wild animals, livestock and human are required.