Inflammatory macrophages prevent colonic goblet and enteroendocrine cell differentiation through Notch signaling.

Inflammatory macrophages in the intestine are a key pathogenic factor driving inflammatory bowel disease (IBD). Here, we report the role of inflammatory macrophage-mediated notch signaling on secretory lineage differentiation in the intestinal epithelium. Utilizing IL-10-deficient (Il10-/-) mice, a model of spontaneous colitis, we found an increase in Notch activity in the colonic epithelium as well as an increase in intestinal macrophages expressing Notch ligands, which are increased in macrophages upon inflammatory stimuli. Furthermore, a co-culture system of inflammatory macrophages and intestinal stem and proliferative cells during differentiation reduced goblet and enteroendocrine cells. This was recapitulated when utilizing a Notch agonist on human colonic organoids (colonoids). In summary, our findings indicate that inflammatory macrophages upregulate notch ligands that activate notch signaling in ISC via cell-cell interactions, which in turn inhibits secretory lineage differentiation in the gastrointestinal (GI) tract.

Video selection and assessment for an app-based HIV prevention messaging intervention: formative research.

Background: Gay, bisexual, and other men who have sex with men (GBMSM) continue to be overrepresented in human immunodeficiency virus (HIV) infection in the United States. HIV prevention and care interventions that are tailored to an individual's serostatus have the potential to lower the rate of new infections among GBMSM. Mobile technology is a critical tool for disseminating targeted messaging and increasing uptake of basic prevention services including HIV testing, sexually transmitted infection (STI) testing, and pre-exposure prophylaxis (PrEP). Mobile Messaging for Men (M-Cubed) is a mobile health HIV prevention intervention designed to deliver video- and text-based prevention messages, provide STI and HIV information, and link GBMSM to prevention and healthcare resources. The current report describes an iterative process of identifying and selecting publicly available videos to be used as part of the M-Cubed intervention. We also conducted interviews with GBMSM to assess the acceptability, comprehension, and potential audience reach of the selected video messages. Methods: The selection of videos included balancing of specific criteria [e.g., accuracy of scientific information, video length, prevention domains: HIV/STI testing, antiretroviral therapy (ART), PrEP, engagement in care, and condom use] to ensure that they were intended for our GBMSM audiences: HIV-negative men who engage in condomless anal sex, HIV-negative men who do not engage in condomless anal sex, and men living with HIV. This formative study included in-person interviews with 26 GBMSM from three U.S. cities heavily impacted by the HIV epidemic-New York City, Detroit, and Atlanta. Results: Following a qualitative content analysis, the study team identified five themes across the interviews: participant reactions to the video messages, message comprehension, PrEP concerns, targeting of video messaging, and prompted action. Conclusions: Study results informed a final selection of 12 video messages for inclusion in a randomized controlled trial of M-Cubed. Findings may serve as a guide for researchers who plan to develop HIV prevention interventions that utilize publicly available videos to promote behavioral change. Further, the findings presented here suggest the importance of developing videos with broad age and gender diversity for use in interventions such as M-Cubed, and in other health promotion settings.

Alterations in the cutaneous microbiome of patients with psoriasis and psoriatic arthritis reveal similarities between non-lesional and lesional skin.

OBJECTIVES: To investigate the cutaneous microbiome spanning the entire psoriatic disease spectrum, and to evaluate distinguishing features of psoriasis (PsO) and psoriatic arthritis (PsA). METHODS: Skin swabs were collected from upper and lower extremities of healthy individuals and patients with PsO and PsA. Psoriatic patients contributed both lesional (L) and contralateral non-lesional (NL) samples. Microbiota were analysed using 16S rRNA sequencing. RESULTS: Compared with healthy skin, alpha diversity in psoriatic NL and L skin was significantly reduced (p<0.05) and samples clustered separately in plots of beta diversity (p<0.05). Kocuria and Cutibacterium were enriched in healthy subjects, while Staphylococcus was enriched in psoriatic disease. Microbe-microbe association networks revealed a higher degree of similarity between psoriatic NL and L skin compared with healthy skin despite the absence of clinically evident inflammation. Moreover, the relative abundance of Corynebacterium was higher in NL PsA samples compared with NL PsO samples (p<0.05), potentially serving as a biomarker for disease progression. CONCLUSIONS: These findings show differences in diversity, bacterial composition and microbe-microbe interactions between healthy and psoriatic skin, both L and NL. We further identified bacterial biomarkers that differentiate disease phenotypes, which could potentially aid in predicting the transition from PsO to PsA.

Monocyte Distribution Width Predicts Sepsis, Respiratory Failure, and Death in COVID-19.

Introduction Sepsis is the leading cause of hospital mortality nationwide. Early recognition has been shown to improve outcomes. This research investigates the use of monocyte distribution width's (MDW) ability to detect sepsis and clinically correlate to outcomes in COVID-19 infection. Methods This is a retrospective, single-center cohort study of adult patients with confirmed COVID-19 requiring hospital admission over a 14-month period (September 2020 to November 2021). MDW was evaluated as a cytomarker to predict disease severity, mortality, and determination of sepsis in patients with COVID-19. Additionally, MDW was compared to existing inflammatory markers, including procalcitonin, D-dimer, ferritin, and lactic acid. Results MDW was able to predict sepsis in patients with COVID-19. The average MDW was found to be significantly higher in the detection of sepsis (25.50 ± 5.93) vs. patients without (23.13 ± 4.46) (p < 0.01). MDW was able to correlate with clinical outcomes or respiratory failure/hypoxia and death. An MDW value of 24.9 was shown to be the best cut-off value in determining fatal outcomes; receiver operating characteristic curve analysis revealed an area under the curve value of 0.69 (95% CI: 0.55-0.71) with a sensitivity of 83% and specificity of 71%. A chi-square test was performed, which detected a significant association between MDW values and the final clinical outcome of COVID-19 (OR = 3.52, 95% CI: 1.78-7.11, p < 0.001). Additionally, the mean MDW of patients with hypoxia or respiratory failure was significantly higher (22 vs. 25, p < 0.1). MDW did not correlate with any of the existing inflammatory markers. Conclusion MDW is a novel and reliable cytomarker for identifying sepsis in patients with COVID-19 infection. High MDW values are associated with clinical outcomes of respiratory failure and death with a mortality rate or absolute risk of 25%. MDW is easily obtained from routine laboratory evaluation in the emergency room and has the potential to be a useful tool in the triage of COVID-19 patients.

Factors associated with age of diagnosis of autism spectrum disorder among children in Saudi Arabia: new insights from a cross-sectional study.

OBJECTIVES: Research examining the age of diagnosis of autism spectrum disorder (ASD) and its influencing factors mostly originate from developed Western countries, providing little to no systematic information about the understanding and management of ASD in the rest of the world. The present exploratory study examined the influence of child and family characteristics on the age of ASD diagnosis in Saudi Arabia. RESULTS: The median age at diagnosis was 3.0 years and was associated with some child and family characteristics. A 1 year increase in child's age was associated with a 0.1 year increase in age of diagnosis (95% CI 0.05, 0.12). Children who did not respond to their name were diagnosed 0.3 years earlier than other children (95% CI - 0.60, - 0.05), and engaging in challenging behavior was associated with a 0.5 year increase in age of diagnosis (95% CI 0.20, 0.81). A lack of comorbidity was associated with a 0.6 year increase in the age of diagnosis compared to the diagnosis age of children with comorbidity (95% CI 0.13, 1.01). Finally, those residing outside of Saudi Arabia were diagnosed with ASD 0.9 years earlier than those residing in Saudi Arabia (95% CI - 0.171, - 0.11).

Low incidence and transient elevation of autoantibodies post mRNA COVID-19 vaccination in inflammatory arthritis.

OBJECTIVES: Autoantibody seroconversion has been extensively studied in the context of COVID-19 infection but data regarding post-vaccination autoantibody production is lacking. Here we aimed to determine the incidence of common autoantibody formation following mRNA COVID-19 vaccines in patients with inflammatory arthritis (IA) and in healthy controls. METHODS: Autoantibody seroconversion was measured by serum ELISA in a longitudinal cohort of IA participants and healthy controls before and after COVID-19 mRNA-based immunization. RESULTS: Overall, there was a significantly lower incidence of ANA seroconversion in participants who did not contract COVID-19 prior to vaccination compared with those who been previously infected (7.4% vs 24.1%, P = 0.014). Incidence of de novo anti-CCP seroconversion in all participants was low at 4.9%. Autoantibody levels were typically of low titre, transient, and not associated with increase in IA flares. CONCLUSIONS: In both health and inflammatory arthritis, the risk of autoantibody seroconversion is lower following mRNA-based immunization than following natural SARS-CoV-2 infection. Importantly, seroconversion does not correlate with self-reported IA disease flare risk, further supporting the encouragement of mRNA-based COVID-19 immunization in the IA population.

Preparing for the Second Surge: Preventing Posttraumatic Stress Disorder and Building Resilience for Health Care Workers in the Face of COVID-19.

The global community needs to be aware of the potential psychosocial consequences that may be experienced by health care workers who are actively managing patients with coronavirus disease (COVID-19). These health care workers are at increased risk for experiencing mood and trauma-related disorders, including posttraumatic stress disorder (PTSD). In this concept article, strategies are recommended for individual health care workers and hospital leadership to aid in mitigating the risk of PTSD, as well as to build resilience in light of a potential second surge of COVID-19.

Non-autophagy Role of Atg5 and NBR1 in Unconventional Secretion of IL-12 Prevents Gut Dysbiosis and Inflammation.

Intestinal myeloid cells play a critical role in balancing intestinal homeostasis and inflammation. Here, we report that expression of the autophagy-related 5 [Atg5] protein in myeloid cells prevents dysbiosis and excessive intestinal inflammation by limiting IL-12 production. Mice with a selective genetic deletion of Atg5 in myeloid cells [Atg5ΔMye] showed signs of dysbiosis preceding colitis, and exhibited severe intestinal inflammation upon colitis induction that was characterised by increased IFNγ production. The exacerbated colitis was linked to excess IL-12 secretion from Atg5-deficient myeloid cells and gut dysbiosis. Restoration of the intestinal microbiota or genetic deletion of IL-12 in Atg5ΔMye mice attenuated the intestinal inflammation in Atg5ΔMye mice. Additionally, Atg5 functions to limit IL-12 secretion through modulation of late endosome [LE] acidity. Last, the autophagy cargo receptor NBR1, which accumulates in Atg5-deficient cells, played a role by delivering IL-12 to LE. In summary, Atg5 expression in intestinal myeloid cells acts as an anti-inflammatory brake to regulate IL-12, thus preventing dysbiosis and uncontrolled IFNγ-driven intestinal inflammation.

Practical Solutions for Healthcare Worker Protection During the COVID-19 Pandemic Response in the Ambulatory, Emergency, and Inpatient Settings.

OBJECTIVE: Protecting healthcare workers is an essential component of a successful response to the COVID-19 pandemic. The resource intensive nature of infectious disease protection, budgetary constraints, and global shortages of personal protective equipment (PPE) make this a daunting task. Practical, easily implemented strategies for healthcare workers (HCW) protection are needed. METHODS: We cross-reference the "Systems, Space, Staff, and Stuff" paradigm from disaster management and the "Hierarchy of Controls" approach to infection prevention from the Center for Disease Control and Prevention (CDC) to generate a narrative overview of worker protection strategies relevant to COVID-19. RESULTS: Alternative types of PPE, management of hazards, and reorganizing how people work can optimize HCWs protection. CONCLUSIONS: A comprehensive PPE strategy can utilize the "systems, space, staff, stuff" paradigm of disaster management to identify new or underutilized solutions to HCWs protection.

Bimetallic Rod-Packing Metal-Organic Framework Combining Two Charged Forms of 2-Hydroxyterephthalic Acid.

Although many rod-packing metal-organic frameworks are known, few are based on ordered heterometallic rod building unit. We show here the synthesis of CPM-76 based on an unprecedented Zn-Mg bimetallic rod with crystallographically distinguishable metal sites. The configuration of the rod offers two types of coordination site with trigonal bipyramidal and octahedral sites selectively occupied by Zn and Mg, respectively. Also unusual is the inter-connection mode between the rods, which is based on dual-charged forms (-3 and -2) of the 2-hydroxyterephthalic acid (H3 OBDC) ligand. Interestingly, each metal site in CPM-76 binds one solvent molecule, leading to a high density of solvent binding sites.

Assessment of Parental Acceptability and Preference for Behavioral Interventions for Feeding Problems.

The present study evaluates the treatment acceptability and preference for behavioral interventions for feeding problems with parents of children with Autism Spectrum Disorder and other developmental disabilities. The impact of behavioral severity on acceptability and preference was also evaluated by comparing results of parents who responded with respect to a vignette of a child with food refusal with those who responded to a vignette of a child with food selectivity. Overall, parents rated differential reinforcement of alternative behavior as the most preferred and most acceptable strategy across both food selectivity and food refusal groups. Escape extinction was the least acceptable and least preferred across both groups, and the severity of the behavior had no impact on acceptability or preference scores. Implications for future research on the social validity of feeding interventions are provided.

Adapting an evidence-based intervention for HIV to avail access to testing and risk-reduction counseling for female victims of sexual violence in post-earthquake Haiti.

Haiti has the highest prevalence of HIV/AIDS in the Caribbean. Before the 2010 earthquake, Haitian women bore a disproportionate burden of HIV/AIDS, had lower HIV knowledge, less capacity to negotiate for safer sex, and limited access to HIV testing and risk-reduction (RR) counseling. Since 2010, there has been an increase in sexual violence against women, characterized by deliberate vaginal injuries by non-intimate partners, increasing victims' risk of sexually transmitted infections including HIV/AIDS. Needed is an adaptation of evidence-based interventions for HIV that include HIV testing and counseling for this stigmatized population. We reviewed several features of Centers for Disease Control and Prevention's 103 evidence-based interventions for HIV (e.g., measures used, participant risk characteristics, theoretical framework, outcome variables, and evidence tier) in an attempt to seek a feasibly adaptable evidence-based intervention for HIV that could be used for victims of sexual violence (VOSV). RESPECT, one of the reviewed evidence-based HIV interventions, comprises of one-on-one, client-focused HIV prevention/RR counseling, and RAPID HIV testing. Adapting RESPECT can enhance access to testing for Haitian VOSV and can influence their perceptions of HIV risk, and establishment of RR goals for future consensual intimate relations. Adapting and implementing RESPECT can increase uptake of evidence-based HIV interventions among Haitians and positively affect a region with high HIV prevalence and increased rates of sexual violence.

Pathogenesis of autosomal dominant hereditary spastic paraplegia (SPG6) revealed by a rat model.

Hereditary spastic paraplegias (HSPs) are characterized by progressive spasticity and weakness in the lower extremities that result from length-dependent central to peripheral axonal degeneration. Mutations in the non-imprinted Prader-Willi/Angelman syndrome locus 1 (NIPA1) transmembrane protein cause an autosomal dominant form of HSP (SPG6). Here, we report that transgenic (Tg) rats expressing a human NIPA1/SPG6 mutation in neurons (Thy1.2-hNIPA1) show marked early onset behavioral and electrophysiologic abnormalities. Detailed morphologic analyses reveal unique histopathologic findings, including the accumulation of tubulovesicular organelles with endosomal features that start at axonal and dendritic terminals, followed by multifocal vacuolar degeneration in both the CNS and peripheral nerves. In addition, the NIPA1 mutation in the spinal cord from older Tg rats results in an increase in bone morphogenetic protein type II receptor expression, suggesting that its degradation is impaired. This Thy1.2-hNIPA1 Tg rat model may serve as a valuable tool for understanding endosomal trafficking in the pathogenesis of a subgroup of HSP with an abnormal interaction with bone morphogenetic protein type II receptor, as well as for developing potential therapeutic strategies for diseases with axonal degeneration and similar pathogenetic mechanisms.